* 603149

INTERLEUKIN 17A; IL17A


Alternative titles; symbols

IL17
CYTOTOXIC T-LYMPHOCYTE-ASSOCIATED SERINE ESTERASE 8; CTLA8


HGNC Approved Gene Symbol: IL17A

Cytogenetic location: 6p12.2     Genomic coordinates (GRCh38): 6:52,186,375-52,190,638 (from NCBI)


TEXT

Description

IL17 is a proinflammatory cytokine that is secreted primarily by activated T cells and that has been implicated in several important inflammatory human diseases. IL17 stimulates a variety of cells to produce inflammatory mediators including IL1 (see 147760), TNFA (191160), and chemokines. These events ultimately lead to the recruitment of neutrophils and other leukocytes that is the hallmark of inflammatory disease (summary by Lopez Kostka et al., 2009).


Cloning and Expression

Rouvier et al. (1993) used subtractive library screening to isolate a novel rodent gene, termed CTLA8, that was expressed specifically in cytotoxic T cells. Although Rouvier et al. (1993) described CTLA8 as a mouse gene, Kennedy et al. (1996) showed that it is actually the rat IL17 homolog. Rouvier et al. (1993) noted that the CTLA8 polypeptide sequence is 56.8% identical to that of the immediate-early gene 13 of Herpesvirus saimiri (HVS-13). The CTLA8 3-prime untranslated region contains AU-rich repeats typically found in the mRNA of cytokines and growth factors.

Yao et al. (1995) cloned a human IL17 cDNA. The cDNA encodes a 155-amino acid polypeptide that contains an N-terminal hydrophobic signal sequence. Northern blot analysis revealed that the gene is expressed as a 1.9-kb mRNA in stimulated, but not resting, T cells; the transcript could not be detected in any human tissues. Expressed recombinant IL17 was secreted in both glycosylated and nonglycosylated forms. IL17 protein applied to fibroblasts induced the production of IL6 (147620) and IL8 (146930) and enhanced surface expression of intracellular adhesion molecule-1 (ICAM1; 147840).


Gene Function

Using a mouse coculture system, Kotake et al. (1999) examined the potential role of IL17 in osteoclastogenesis. Treatment of cocultures of mouse hematopoietic cells and primary osteoblasts with recombinant human IL17 induced the formation of multinucleated cells that satisfied major criteria of osteoblasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentin slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin, a selective inhibitor of cyclooxygenase-2 (COX2; 600262). The addition of IL17 increased prostaglandin E2 (PGE2) synthesis in the cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL17 dose-dependently induced expression of osteoclast differentiation factor (ODF; 602642) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF; 602643), a decoy receptor of ODF, completely inhibited IL17-induced osteoclast differentiation in the cocultures.

Kotake et al. (1999) found that levels of IL17 in synovial fluids were significantly higher in rheumatoid arthritis (RA; 180300) patients than in osteoarthritis (165720) patients. Anti-IL17 antibodies significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggested that IL17 first acts on osteoblasts, which stimulates both COX2-dependent PGE2 synthesis and ODF gene expression, which in turn induces differentiation of osteoclast progenitors into mature osteoclasts, and that IL17 is a crucial cytokine for osteoclastic bone resorption in RA patients.

Although there are elevated levels of IL17 in synovial fluid of patients with rheumatoid arthritis, its pathogenic role in that disease remained to be elucidated. Nakae et al. (2003) examined the effects of IL17 deficiency in mice deficient for the IL1 receptor antagonist (IL1Ra -/-; 147679), which spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL1 signaling. IL17 expression is greatly enhanced in these mice, suggesting that IL17 activity is involved in the pathogenesis of the arthritis in these mice. Indeed, Nakae et al. (2003) found that the spontaneous development of arthritis did not occur in IL1 Ra -/- mice also deficient in IL17. Crosslinking OX40 (600315), a cosignaling molecule on CD4+ T cells that plays an important role in T cell antigen-presenting cell interaction, with anti-OX40 antibody accelerated the production of IL17 induced by CD3 stimulation. Because OX40 is induced by IL1 signaling, IL17 induction was thought to be downstream of IL1 through activation of OX40. These observations suggested the IL17 plays a crucial role in T cell activation, downstream of IL1, causing the development of autoimmune arthritis.

Using immunohistochemistry, McAllister et al. (2005) localized IL17R (IL17RA; 605461) to basal airway cells in lung tissue. Both IL17 and IL17F (606496), in synergy with TNF (191160), upregulated GCSF (CSF3; 138970) and GROA (CXCL1; 155730) expression in bronchial epithelial cells in a time-dependent manner via the basolateral, rather than the apical, surfaces of the cells. This upregulation was inhibited by anti-IL17R, but only IL17 was inhibited by soluble IL17R. Immunohistochemical and functional analyses demonstrated basolateral expression of TNFR1 (TNFRSF1A; 191190) and TNFR2 (TNFRSF1B; 191191). During episodes of pulmonary exacerbation, cystic fibrosis (CF; 219700) patients showed increased IL23 (see 605580), IL17, and IL17F expression, and these levels decreased with antibiotic treatment. McAllister et al. (2005) proposed that targeting IL17 and IL17F or antagonizing IL17R might mitigate neutrophil-mediated inflammation in CF.

Harrington et al. (2005) showed that development of the proinflammatory subset of Il17-secreting T helper cells, which they called Th17 cells, occurred optimally in the presence of Il23 (see IL23A; 605580) in mice, whereas Th1 and Th2 cells responded poorly to Il23. Ifng (147570) and Il4 (147780), inducers of Th1 and Th2 development, respectively, suppressed development of Th17 cells, which were instead derived from naive precursor cells. Type I interferons (e.g., IFNA1; 147660) also inhibited Th17 development. Th17 development was undiminished, and in some cases enhanced, in mouse cells lacking Stat1 (600555), Stat4 (600558), or Tbet (TBX21; 604895), which are necessary for Th1 development, and in cells lacking Stat6 (601512), which is necessary for Th2 development, Differentiated Th17 effector cells were relatively resistant to inhibition by Il4 or Ifng. Harrington et al. (2005) concluded that inhibition of IFNG signaling enhances development of pathogenic Th17 effector cells that exacerbate autoimmunity.

Park et al. (2005) reported findings similar to those of Harrington et al. (2005), but they observed a more potent inhibition of Il23-dependent Il17 production by Il4. In addition, Park et al. (2005) showed that generation of Il17-producing Th cells in mice required costimulation by Cd28 (186760) and Icos. Mice overexpressing Il17 in lung epithelial cells experienced substantial pulmonary pathology accompanied by production of multiple chemokines. Treatment with neutralizing anti-Il17 before or after onset of experimental autoimmune encephalomyelitis inhibited chemokine expression and prevented development of disease. Park et al. (2005) concluded that IL17 is expressed by a novel subset of Th cells and is crucial in regulating tissue inflammatory reactions.

Mangan et al. (2006) showed that exogenous Tgfb (190180) induced development of Th17 cells in Il12b (161561) -/- mice, whose antigen-presenting cells produce neither Il12 or Il23. In Ifng -/- T cells, Tgfb induced expression of Il23r (607562), conferring Il23 responsiveness for Th17 cell development. Challenge of Il12b -/- mice or Il23a -/- mice with a natural rodent pathogen, Citrobacter rodentium, resulted in failure to clear infection and death. In contrast to Il12b -/- mice, Il23a -/- mice did not show impaired induction of an Il17 response. Histopathologic and flow cytometric analysis demonstrated that intestinal tissue was enriched in Th17 cells in wildtype mice, but not in Tgfb -/- mice; Tgfb +/- mice had intermediate levels of Th17 cells. Activation of naive T cells with Tgfb resulted in expression of both intracellular Il17 and Foxp3 (300292), a transcription factor associated with regulatory T cells (Treg cells). Addition of Il6, however, nearly extinguished the Foxp3-positive cells. Mangan et al. (2006) concluded that TGFB plays a dual role in T-cell differentiation by directing distinct populations of FOXP3-positive Treg cells and Th17 cells, contingent upon the inflammatory cytokine environment.

Using flow cytometric, ELISA, immunoprecipitation, and Western blot analyses, Toy et al. (2006) showed that expression of both human IL17RA and IL17RC (610925) on Il17ra-deficient mouse fibroblasts was necessary for either human IL17 or IL17F to fully bind cells and induce secretion of CXCL1. Immunoprecipitation analysis revealed a physical association between IL17RA and IL17RC. Toy et al. (2006) concluded that the functional IL17R is a heteromeric complex consisting of at least IL17RA and IL17RC.

Tan et al. (2006) noted that mice lacking Il17ra have reduced resistance to bacterial and fungal infections. They found that Il17ra -/- mice had normal baseline hematopoiesis, but they were more susceptible to hematopoietic toxicity from gamma irradiation and succumbed at lower levels of radiation than wildtype mice. Neutrophils decreased in a dose-dependent fashion after x-ray treatment. Infusion of Cd4 (186940)-positive T cells following irradiation enhanced hematopoietic recovery in wildtype mice, but not in Il17ra -/- mice or mice treated with anti-Il17ra. Overexpression of Il17a in normal mice also enhanced granulopoiesis following irradiation. Tan et al. (2006) concluded that IL17A is required for recovery of granulopoiesis after radiation injury.

Amadi-Obi et al. (2007) found that Th17 cells were present in human uveitis, as well as in mouse experimental autoimmune uveoretinitis (EAU). Flow cytometric analysis demonstrated that Th17 cell numbers increased during active uveitis and, in peripheral blood cells, were expanded by IL2 (147680) and inhibited by IFNG. Anti-IL17 ameliorated EAU in mice, and IL27 inhibited uveitogenic T cells in an Ifng- and Stat1-dependent manner. Amadi-Obi et al. (2007) proposed that Th1 cells may mitigate uveitis by antagonizing Th17 cells through IFNG, suggesting that antagonism of Th17 by IFNG and/or IL27 may be useful for treatment of chronic inflammation.

Steinman (2007) reviewed the Th17 hypothesis of cell-mediated tissue damage and the paradigm shift from the Th1/Th2 hypothesis developed in the 1980s.

TGF-beta converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of IL6 (147620), TGF-beta also promotes the differentiation of naive T lymphocytes into proinflammatory IL17 cytokine-producing Th17 cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. Mucida et al. (2007) identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL6-driven induction of proinflammatory Th17 cells and promoting antiinflammatory Treg differentiation. Mucida et al. (2007) concluded that a common metabolite can regulate the balance between pro- and antiinflammatory immunity.

Using an in vitro model of the human blood-brain barrier (BBB) with brain-derived microvascular endothelial cells, Kebir et al. (2007) demonstrated that IL17 and IL22 (605330) disrupted BBB tight junctions in vitro. CD45RO (151460)-positive cells expressing IL17 and IL22 were present in multiple sclerosis (MS; see 126200) lesions, and IL17R and IL22R (see 605457) were expressed on BBB endothelial cells in MS lesions, but not control brain material. Th17 lymphocytes transmigrated efficiently across BBB endothelial cells, expressed high levels of granzyme B (GZMB; 123910), killed human neurons, and promoted central nervous system inflammation through CD4-positive lymphocyte recruitment.

Using flow cytometry and ELISA, Sato et al. (2007) found that CCR2 (601267)-positive, but not CCR2-negative, CD4-positive T cells produced IL17. Within the CCR2-positive population, CCR5 (601373)-positive cells produced IFNG and CCR5-negative cells produced IL17. Sato et al. (2007) concluded that human Th17 cells are CCR2-positive/CCR5-negative.

Coury et al. (2008) detected high levels of soluble RANKL (TNFSF11; 602642) and IL17A, but not IL1B (147720), IL22, or TNF, in serum from patients with Langerhans cell histiocytosis (LCH; 604856). Immunohistochemical analysis demonstrated IL17A-positive dendritic cells (DCs) in LCH patient skin and bone lesions and in multinucleated giant cells (MGCs). Intracytoplasmic flow cytometry and ELISA identified DCs, and not T cells, as the source of IL17A in LCH. IL17A stimulation induced fusion of healthy DCs in vitro. LCH DCs behaved similarly to IL17A-stimulated healthy DCs, and transwell assays confirmed that IL17A secreted from LCH DCs was functional. Gene chip analysis showed that IL17A was responsible for expression of TRAP (ACP5; 171640), MMP9 (120361), and MMP12 (601046) by MGCs in healthy DCs. Healthy DCs treated with IL17A and LCH DCs and MGCs displayed overactivation of TRAP. IgG autoantibody to IL17A was also detected in LCH serum. Coury et al. (2008) proposed that IL17A has a major role in LCH severity and may be a therapeutic target in the disease. They also suggested that DCs may be effector cells in other IL17A-related diseases.

In a follow-up study to Coury et al. (2008), Allen and McClain (2009) reported that they were unable to detect IL17A mRNA by RT-PCR in CD207 (604862)-positive Langerhans cells or CD3-positive T cells isolated by flow cytometry from 14 LCH biopsy samples. In addition, they could not detect significant levels of serum IL17A in LCH patients. In response, Arico et al. (2009) pointed out that they (i.e., Coury et al. (2008)) had detected IL17A in CD207-negative DCs, the majority cell population in LCH lesions, using different sets of antibodies from those used by Allen and McClain (2009). They also stated that their serum ELISA assay used a capture antibody able to outcompete autoantibodies to IL17A that are present in LCH sera. Both studies showed that serum IL17A concentrations did not correlate with LCH activity and that Th17 cells were not present in LCH lesions. Indirectly, there may also be concurrence between the studies in the statement by Arico et al. (2009) that LCH is a DC-related disease rather than a Langerhans cell-related disease.

Milner et al. (2008) showed that interleukin IL17 production by T cells is absent in individuals with hyper-IgE syndrome (HIES; 147060). They observed that ex vivo T cells from subjects with HIES failed to produce IL17, but not IL2 (147680), TNF (191160), or IFNG (147570), on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL17-producing (TH17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gamma-t (602943), which is consistent with a crucial role for STAT3 (102582) signaling in the generation of TH17 cells. TH17 cells are an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial infections. Thus, Milner et al. (2008) concluded that the inability to produce TH17 cells is a mechanism underlying the susceptibility to recurrent infections commonly seen in HIES.

Atarashi et al. (2008) found that cells expressing Il17, Rorc, and Il17f constituted a large proportion of Cd4-positive T cells in the intestinal lamina propria of mice. These 'naturally occurring' Th17 cells were selectively and constitutively present, even under specific-pathogen-free conditions, and their numbers increased with age. Flow cytometric analysis showed that Th17 numbers were reduced in the lamina propria of germ-free mice, but ATP, derived from commensal bacteria or administered systemically or rectally, caused an increase in lamina propria Th17 cells that was mediated by Cd70 (TNFSF7; 602840)-high/Cd11c (ITGAX; 151510)-low myeloid cells expressing P2x (e.g., P2RX2; 600844) and P2y (e.g., P2RY6; 602451) receptors, as well as Il6, Il23p19, Itgav (193210), and Itgb8 (604160). Furthermore, administration of ATP exacerbated a T cell-mediated colitis model with enhanced Th17 differentiation. Atarashi et al. (2008) concluded that commensal bacteria and ATP are important for Th17 differentiation in health and disease, and that they may explain why Th17 cells are present specifically in the intestinal lamina propria.

Torchinsky et al. (2009) demonstrated that the physiologic stimulus necessary to trigger a Th17 response is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL6 and transforming growth factor-beta (190180) through recognition of pathogen-associated molecular patterns and phosphatidylserine exposed on apoptotic cells, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium, which models human infections with the attaching and effacing enteropathogenic and enterohemorrhagic E. coli, impairs the characteristic Th17 response in the lamina propria. Torchinsky et al. (2009) concluded that their results demonstrated that infected apoptotic cells are a critical component of the innate immune signals instructing Th17 differentiation, and pointed to pathogens particularly adept at triggering apoptosis that might preferentially induce Th17-mediated immunity. Torchinsky et al. (2009) proposed that because Th17 cells have been correlated with autoimmune diseases, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.

Using predominantly wildtype and Hif1a (603348) -/- mouse T cells, Dang et al. (2011) showed that Hif1a was specifically required for differentiation of naive T cells into Th17 cells. Hif1a interacted directly with Ror-gamma-t and acetyltransferase p300 (EP300; 602700) at the Il17 promoter, and all 3 factors were required for optimum Il17 expression. Simultaneously, Hif1a downregulated differentiation of naive T cells into Treg cells by directing proteasomal degradation of Foxp3 by a mechanism that was independent of Hif1a transcriptional activity. Differentiation of Th17 cells and loss of Treg cells was enhanced in cultures subjected to hypoxic conditions. Knockout of Hif1a in mouse T cells rendered mice highly resistant to Mog (159465)-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Dang et al. (2011) concluded that HIF1A has a role in immune responses by controlling the balance between Th17 and Treg cells.

Using Lxra (NR1H3; 602423) and Lxrb (NR1H2; 600380) double-knockout mice and Lxr agonists, Cui et al. (2011) observed Lxr-dependent amelioration of experimental autoimmune encephalomyelitis. Lxr overexpression decreased, whereas Lxr deficiency promoted, cytokine-driven mouse Th17 cell differentiation and polarization in vitro. In mouse, Srebp1 (SREBF1; 184756) was recruited to the E-box element on the Il17 promoter upon Lxr activation and interacted with Ahr (600253) to inhibit Il17 transcriptional activity. LXR activation in human cells also suppressed Th17 cell differentiation, promoted SREBP1 expression, and decreased AHR expression. Mutation and coimmunoprecipitation analyses showed that the putative active-site domain of mouse Ahr and the N-terminal acidic region of mouse Srebp1 were essential for Ahr-Srebp1 interaction. Cui et al. (2011) concluded that a downstream target of LXR, SREBP1, antagonizes AHR to suppress Th17 cell generation and autoimmunity.

Using an approach that combined the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, Zielinski et al. (2012) described 2 types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL17 and IFN-gamma but no IL10 (124092), whereas Staphylococcus aureus-specific TH17 cells produced IL17 and could produce IL10 upon restimulation. IL6 (147620), IL23 (see 605580), and IL1-beta (147720) contributed to TH17 differentiation induced by both pathogens, but IL1-beta was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL12 (see 161561) and to prime IL17/IFN-gamma double-producing cells. In addition, IL1-beta inhibited IL10 production in differentiating and in memory TH17 cells, whereas blockade of IL1-beta in vivo led to increased IL10 production by memory TH17 cells. Zielinski et al. (2012) showed that, after restimulation, TH17 cells transiently downregulated IL17 production through a mechanism that involved IL2 (147680)-induced activation of STAT5 (601511) and decreased expression of ROR-gamma-t. Zielinski et al. (2012) concluded that, taken together, their findings demonstrated that by eliciting different cytokines, C. albicans and S. aureus prime TH17 cells that produce either IFN-gamma or IL10, and identified IL1-beta and IL2 as pro- and antiinflammatory regulators of TH17 cells both at priming and in the effector phase.

Grivennikov et al. (2012) investigated mechanisms responsible for tumor-elicited inflammation in a mouse model of colorectal tumorigenesis which, like human colorectal cancer, exhibits upregulation of IL23 and IL17. They showed that IL23 signaling promotes tumor growth and progression, and development of tumoral IL17 response. IL23 is mainly produced by tumor-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumors but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. Grivennikov et al. (2012) proposed that barrier deterioration induced by colorectal cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumor-elicited inflammation, which in turn drives tumor growth.

Santarlasci et al. (2012) noted that Th17 cells have a critical pathogenic role in chronic inflammatory disorders, but they are rarely found in inflammatory sites. Santarlasci et al. (2012) found that, unlike Th1 cells, human CD161 (KLRB1; 602890)-positive Th17 precursor cells did not proliferate and produce IL2 in response to anti-CD3/anti-CD28 stimulation. Th17 cells also proliferated poorly in response to IL2, in part due to lower expression of the transcription factors JUN (165160), FOS (164810), and NFATC1 (600489) and reduced surface expression of CD3E (186830) and CD3Z (CD247; 186780). Microarray and small interfering RNA analyses revealed high expression of IL4I1 (609472) in Th17 precursor cells and showed that IL4I1 upregulation was strictly dependent on RORC (602943), the Th17 master regulatory gene. Flow cytometric analysis revealed that Th17 cells also exhibited high CD28 expression that was RORC dependent, and stimulation of CD28 alone induced IL17 production and IL4I1 mRNA upregulation. Th17 cells from synovial fluid of patients with juvenile idiopathic arthritis (see 604302) also expressed higher levels of IL4I1 and CD28 than did Th1 cells. Santarlasci et al. (2012) concluded that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms that limit their expansion and, therefore, reduce their potential to cause damage.

By stimulating T cells from mice with a conditional knockout of Egr2 (129010), Miao et al. (2013) observed high induction of Il1, Il17, and Il21 (605384), but not Il2 or Ifng. Egr2, but not other EGR genes, was induced in naive mouse T cells by the Th17-cell inducers Tgfb and Il6, but not by Ifng or Il4, which promote Th1 and Th2 cells, respectively. Although expression of Th17 regulatory factors was not affected in Egr2-deficient Th17 cells, binding of Batf (612476) to DNA-binding sites in the Il17 promoters was significantly increased in Egr2-deficient Th17 cells. Mice lacking Egr2 were susceptible to induction of experimental autoimmune encephalomyelitis. Stimulated CD4 T cells from patients with multiple sclerosis showed normal expression of BATF, significantly reduced expression of EGR2, and increased expression of IL17. Miao et al. (2013) concluded that EGR2 is involved in regulation of Th17 cytokine production and Th17 differentiation by inhibiting BATF function and that EGR2 is important in the control of autoimmunity and inflammation.

Ling et al. (2013) found that treatment of a mouse macrophage cell line with Il17a prior to infection with the avirulent M. bovis BCG vaccine strain enhanced BCG-induced nitric oxide (NO) production and inducible NO synthase (NOS2A; 163730) expression in a dose- and time-dependent manner. The effect was not observed in human monocyte-derived macrophages. The synergism in mouse macrophages appeared to be mediated by enhanced BCG-induced phosphorylation of Jnk (MAPK8; 601158), but not of Erk1 (MAPK3; 601795), Erk2 (MAPK1; 176948), or p38 (MAPK14; 600289). Treatment with a Jnk inhibitor suppressed NO production in BCG-treated macrophages. Ling et al. (2013) concluded that the Jnk pathway is involved in Il17a-enhanced NO production in BCG-infected mouse macrophages and that Il17a enhances the clearance of BCG by macrophages through an NO-dependent killing mechanism.

By RT-PCR and flow cytometric analyses, Gosmann et al. (2014) detected elevated expression of IL17 and IL23 in human precancerous cervical intraepithelial neoplasia (CIN) compared with control cervical tissue. Expression of Il17 and Il23 was also elevated in the skin of transgenic mice expressing the human papillomavirus (HPV) protein E7 compared with control mouse skin. Transplant of E7 transgenic skin from mice lacking Il17, but not from mice heterozygous for Il17, resulted in rejection by controls. CD4-positive T cells were the predominant source of IL17 in human CIN, and CD4-positive and gamma/delta T cells were the predominant sources of Il17 in transgenic mouse skin. Production of Il17 was induced by Il23 and Il1b, but not by Il18 (600953), in E7 transgenic skin. Gosmann et al. (2014) concluded that IL17 mediates immunosuppression in HPV-associated epithelial neoplasia. They proposed that IL17 blockade may be of therapeutic use in persistent infection with high-risk HPV strains and may prevent progression to malignant lesions.

Kshirsagar et al. (2014) reported that enhanced STAT3 activity in CD4-positive/CD45A (see 151460)-negative/FOXP3-negative and FOXP3-low effector T cells from children with lupus nephritis (LN; see 152700) correlated with increased frequency of IL17-producing cells within these T-cell populations. Rapamycin treatment reduced both STAT3 activation and Th17 cell frequency in lupus patients. Th17 cells from children with LN exhibited high AKT (164730) activity and enhanced migratory capacity. Inhibition of AKT in cells from LN patients resulted in reduced Th17-cell migration. Kshirsagar et al. (2014) concluded that the AKT signaling pathway plays a significant role in Th17-cell migratory activity in children with LN. They suggested that inhibition of AKT may result in suppression of chronic inflammation in LN.

Erbel et al. (2014) found that treatment of mature Apoe (107741)-null mice for 6 weeks with anti-Il17a prevented atherosclerotic lesion progression and improved lesion stability via reduction in inflammatory burden and cellular infiltration. Experiments in vitro showed that IL17A played a role in chemoattraction, monocyte adhesion, and antigen-presenting cell sensitization toward pathogen-derived TLR4 (603030) ligands. Stimulation of human carotid plaque tissue ex vivo with IL17A induced a proinflammatory milieu. Erbel et al. (2014) concluded that IL17A is an important proatherogenic cytokine that may be an attractive therapeutic target for preventing atherosclerotic lesion progression.

Rutz et al. (2015) showed that the deubiquitylating enzyme DUBA (OTUD5; 300713) is a negative regulator of IL17A production in T cells. Mice with Duba-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. Duba interacted with the ubiquitin ligase Ubr5 (608413), which suppressed Duba abundance in naive T cells. Duba accumulated in activated T cells and stabilized Ubr5, which then ubiquitylated ROR-gamma-t in response to TGFB (190180) signaling. Rutz et al. (2015) concluded that their data identified DUBA as a cell-intrinsic suppressor of IL17 production.

Using mouse models of spontaneous breast cancer metastasis, Coffelt et al. (2015) demonstrated that breast tumors maximize their chance of metastasizing by invoking a systemic inflammatory cascade. Coffelt et al. (2015) mechanistically demonstrated that IL1B (147720) elicits IL17 expression from gamma-delta T cells, resulting in systemic granulocyte colony-stimulating factor (GCSF; 138970)-dependent expansion and polarization of neutrophils in mice bearing mammary tumors. Tumor-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen (see 186730), which limit the establishment of metastases. Neutralization of IL17 or GCSF and absence of gamma-delta T cells prevents neutrophil accumulation and downregulates the T cell-suppressive phenotype of neutrophils. Moreover, the absence of gamma-delta T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumor progression. Coffelt et al. (2015) concluded that targeting this novel cancer cell-initiated domino effect within the immune system--the gamma-delta T cell/IL17/neutrophil axis--represents a novel strategy to inhibit metastatic disease.

Using single-cell RNA sequencing analysis of mouse Th17 cells differentiated in vitro under pathogenic versus nonpathogenic conditions or of Th17 cells isolated ex vivo from lymph nodes or central nervous system of mice undergoing experimental autoimmune encephalomyelitis (EAE), Kishi et al. (2016) showed that expression of Procr (600646) correlated inversely with Th17-cell pathogenicity. Procr expression was regulated by transcription factors critical for Th17 differentiation, including Stat3, Irf4 (601900), and Rorgt. Procr overexpression reduced expression of the Th17 proinflammatory module, including Il1r (IL1R1; 147810) and Il23r (607562). Using different EAE mouse models, Kishi et al. (2016) found that loss or reduction of Procr expression led to increased Th17 pathogenicity and enhanced EAE in vivo. Kishi et al. (2016) concluded that PROCR is a negative regulator of Th17 pathogenicity.

Tanaka et al. (2018) showed that conditional knockout of Trim33 (605769) in T cells of mice resulted in decreased Il17 and Ccr6 (601835) expression, but enhanced Il10 production, leading to protection against EAE. Further examination revealed that Trim33 played a crucial role in differentiation of Th17 cells, but not inducible Treg cells. Microarray and real-time RT-PCR analyses confirmed downregulation of Il17 and Ccr6 and upregulation of Il10 in the absence of Trim33. Il17 and Ccr6 downregulation was not due to enhanced Il10 expression, as Il10 blockade did not restore Il17 and Ccr6 expression in Trim33-knockout T cells. Genomewide analysis of Trim33-bound genes showed that Il17 and Il10 were collaboratively regulated by Trim33 and Ror-gamma at the transcriptional level. Trim33 controlled Il17 and Il10 expression at the chromatin level through regulation of histone modifications. Smad2 (601366) was crucial for binding of Trim33 to Il17 and Il10 loci, and the Trim33/Smad2/Ror-gamma complex was necessary for optimal expression of Il17 and repression of Il10 in Th17 cells. Moreover, enhanced expression of Il10 in Trim33-knockout T cells was almost completely suppressed by deletion of Smad4 (600993), indicating that Trim33 suppresses Il10 expression by reduction of Smad4 protein in T cells. The authors concluded that TRIM33 promotes the proinflammatory function of Th17 cells by inducing IL17 and suppressing IL10 expression.


Mapping

Rouvier et al. (1993) used in situ hybridization to map the IL17 gene to human chromosome 2q31 and to mouse chromosome 1A, in a region of known syntenic homology.


Animal Model

Nakae et al. (2002) tested various disease models in Il17-deficient mice and found that Il17 was involved in contact, delayed, and airway hypersensitivity, but not in acute graft-versus-host reaction (see 614395). They proposed that IL17 plays an important role in allergen-specific T cell-mediated immune responses.

Nakae et al. (2003) found that collagen-induced arthritis was markedly reduced in mice lacking Il17. They showed that Il17 was necessary for priming of collagen-specific T cells and IgG2a production.

Using a murine model of acute fatal pneumonia, Priebe et al. (2008) showed that use of an attenuated Pseudomonas aeruginosa strain as a vaccine mediated protection not only against the parental strain, but also against other cytotoxic variants. However, serum from the vaccinated mice had low levels of opsonic antibody but high levels of neutrophils after challenge, and their T cells produced high levels of Il17. Mice lacking Il17r were not protected from virulent challenge. Priebe et al. (2008) concluded that IL17 plays a critical role in antibody-independent vaccine-induced protection against P. aeruginosa in lung.

Lin et al. (2009) noted that IFNG and Th1 immunity are critical for host resistance to the intracellular bacterium Francisella tularensis, the causative agent of tularemia and a potential bioterrorism agent. Using mice lacking various cytokines and ELISPOT analysis, they demonstrated that Il23-dependent Il17a was induced during F. tularensis infection and was required for induction of Il12, optimal induction of Th1 cell responses, and host resistance to infection. Lin et al. (2009) concluded that IL17A, but not IL17F or IL22, functions to regulate IL12-Th1 cell immunity and host responses to an intracellular pathogen.

Lopez Kostka et al. (2009) noted that C57BL/6 mice develop Th1/Tc1 cell-dependent resistance to cutaneous leishmaniasis, whereas BALB/c mice preferentially develop Th2 immunity and succumb to infection. They found that neutrophils and Cd4-positive T cells from BALB/c mice produced increased amounts of Il17 during Leishmania major infection compared with cells from C57BL/6 mice. Correspondingly, BALB/c DCs produced more Il23 than C57BL/6 DCs after L. major infection, whereas Il6 and Tgfb production was comparable in BALB/c and C57BL/6 DCs. Infected Il17 -/- BALB/c mice had smaller, nonprogressing lesions compared with control mice. Amounts of Il4, Il10 (124092), and Ifng produced by T cells were comparable in Il17 -/- and wildtype BALB/c mice. The improved disease outcome was associated with decreased Cxcl2 (139110) accumulation in lesion sites and decreased neutrophil migration into lesions of Il17 -/- mice. Lopez Kostka et al. (2009) proposed that IL23 production by L. major-infected DCs maintains IL17-positive cells that influence disease progression via regulation of neutrophil recruitment.

Kagami et al. (2010) observed delayed healing and decreased Il17a production following skin infection with Candida albicans in mice lacking Il23 or Il17a compared with wildtype mice or mice lacking Il12 or Il22. Histologic analysis revealed epidermal hyperplasia overlying infected dermis in wildtype mice, but fungal burden was greater and epidermal hyperplasia was severely reduced in Il23 -/- mice. Il23 -/- mice also failed to express Il17a or Il22 mRNA. Injection of recombinant Il17a promoted rapid healing in wildtype mice and mice lacking Il23 or Il12. Kagami et al. (2010) concluded that IL23 and IL17A, but not IL12 or IL22, are required for optimal host defense against cutaneous candidiasis. They also proposed that cutaneous candidiasis may be treatable with recombinant IL17A.

By flow cytometric analysis, Mayuzumi et al. (2010) found constitutive Il17a production in mouse lamina propria, Peyer patch, and mediastinal lymph node, but not in intraepithelial T lymphocytes. Ifng production was induced by Salmonella enterica (Typhimurium) infection in gut-associated lymphoid tissue. Neutralization of Il17 suppressed induction of the antimicrobial peptide, beta-defensin-3 (DEFB103A; 606611) at the site of the intestinal mucosa. Mayuzumi et al. (2010) proposed that IL17 participates in the immediate-early stage of protection against S. typhimurium intestinal infection, whereas IFNG is important at later stages of infection.

Geddes et al. (2011) infected mice with Citrobacter rodentium or Salmonella typhimurium species and observed triggering of early Il17 production that was crucial for host defense mediated by Cd4-positive helper T cells. Th17 responses occurred principally in the cecum and were mediated by innate Th17 cells that were regulated by Nod1 (605980) and Nod2 (605956). Mice lacking both Nod1 and Nod2 were unable to induce early Th17 responses due to insufficient Il6 production. Geddes et al. (2011) concluded that the NOD-innate Th17 axis, which is dependent on IL6 expression and requires intestinal microbiota for induction, is a key element of mucosal immunity against bacterial pathogens.

After injecting mice with anti-CD3 (see 186740) antibody, Esplugues et al. (2011) observed the expected rapid disappearance of most T cells from circulation. However, they also found a concomitant increase in the percentage and number of total T cells in the small intestine, in particular in the duodenum. Immunofluorescence microscopy showed a high frequency of Th17 cells in small intestine. Th17 cell induction was Il6 dependent. Il17 signaling, in turn, led to upregulation of Ccl20 (601960), facilitating migration of Th17 cells to the small intestine. Mouse models of sepsis and influenza A virus infection showed that proinflammatory Th17 cells could be redirected to and controlled in the small intestine. In addition, the proinflammatory cells simultaneously acquired a regulatory phenotype. Esplugues et al. (2011) concluded that Th17 cells, which are beneficial in clearing infection, can be prevented from becoming immunopathogenic by acquiring an immune-suppressive phenotype or by elimination into the intestinal lumen.

Kudva et al. (2011) found that mice lacking Il17a, Il17f, Il17ra, or Il22, all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I and type II IFN in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.

Chen et al. (2012) studied Th2-type immune responses in a mouse model of intestinal nematode parasite infection in which parasite larvae migrate transiently through lung. They found that acute lung injury occurred shortly after worm inoculation and was associated with hemorrhaging, inflammation, decreased lung function, and Ill7 expression. Subsequent Il4r (147781) signaling reduced Il17 expression, enhanced expression of Igf1 (147440) and Il10, and stimulated development of M2-type macrophages, all of which contributed to rapid resolution of tissue damage.

Using chromosome conformation capture, Wang et al. (2012) demonstrated that a cis element, which they termed conserved noncoding sequence-2 (CNS2), located upstream of the Il17 promoter, interacted with the Il17 promoter and also with that for Il17f. Mice lacking Cns2 had impaired Rorc-driven Il17 and Il17f expression in vitro. These cytokine defects were associated with defective chromatin remodeling of the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and Jmjd3 (KDM6B; 611577). CNS2-deficient mice were also resistant to experimental autoimmune encephalomyelitis. Wang et al. (2012) proposed that CNS2 is sufficient and necessary for IL17 and optimal IL17F gene transcription in Th17 cells.

Barin et al. (2013) reported that mice lacking Ifng developed severe experimental autoimmune myocarditis (EAM) following immunization with cardiac myosin peptide (residues 614 to 629 of MYH6, 160710). In contrast, mice lacking Il17a were protected from progression to dilated cardiomyopathy. Double-knockout (DKO) mice lacking both Il17a and Ifng developed rapidly fatal EAM following immunization. Eosinophils constituted one-third of infiltrating leukocytes, allowing the condition to be characterized as eosinophilic myocarditis. Infection of DKO mice with coxsackie virus B3, which is associated with myocarditis in both humans and mouse models, resulted in a similar form of EAM. Flow cytometric analysis of infiltrating Cd4 T cells demonstrated production of Ccl11 (601156), as well as Th2 deviation. DKO mice that also carried a deletion of the high-affinity double GATA-binding site in the Gata1 (305371) promoter, which ablates eosinophil generation, demonstrated improved survival and were at least partially protected from fatal heart failure. Barin et al. (2013) concluded that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.

Tong et al. (2015) found that Il17 -/- mice exhibited attenuated hyperglycemia and insulitis, with fewer Cd8-positive cells infiltrating pancreas, compared with wildtype mice following streptozotocin (STZ)-induced diabetes. Wildtype mice, but not Il17 -/- mice, had increased splenic Cd8-positive cells and decreased Gr1-positive/Cd11b (ITGAM; 120980)-positive myeloid-derived suppressor cells (MDSCs) after STZ treatment. MDSCs from Il17-/- mice showed increased ability to suppress Cd8-positive cell proliferation in vitro and, when transferred to diabetic mice, ameliorated hyperglycemia and reduced splenic Cd8-positive cells. Tong et al. (2015) concluded that Il17 has a pathogenic role in STZ-induced diabetes.

Wynn et al. (2016) found that Il18 -/- neonatal mice were highly protected from polymicrobial sepsis, whereas replenishment of Il18 increased lethality to sepsis or endotoxemia. Increased lethality depended on increased Il1r1 (147810) signaling, but not adaptive immunity. Transcriptomic analysis of human neonates with sepsis revealed elevated levels of IL18, IL18R1 (604494), and IL18RAP (604509), and pathway analysis identified a role for IL17R. In mice, plasma Il17a produced by lamina propria and lung parenchyma cells was significantly amplified following exposure to Il18 and sepsis. Anti-Il17ra blockade or deletion of Il17a ablated the deleterious effects of Il18 on sepsis mortality in mice. Wynn et al. (2016) concluded that IL17A is an effector of IL18-mediated injury in neonatal sepsis and proposed that disruption of the tissue-destructive IL18-IL1-IL17A axis may be a therapeutic approach to improve outcomes in neonatal sepsis.

Using maternal immune activation (MIA) in a mouse model of autism spectrum disorder (ASD; 209850) and genetic mutant mice, Choi et al. (2016) showed that Rorgt-dependent effector T lymphocytes, such as Th17 cells, and Il17a were required in mothers for MIA-induced behavioral abnormalities in offspring. MIA induced a maternal Il17a-dependent abnormal phenotype in cortex of fetal brain. Treating pregnant female mice with antibodies blocking Il17a ameliorated MIA-associated behavioral abnormalities. Choi et al. (2016) proposed that targeting of Th17 cells in susceptible pregnant mothers may reduce the likelihood of them bearing children with inflammation-induced ASD-like phenotypes.

Reed et al. (2020) compared an environmental model of neurodevelopmental disorders in which mice were exposed to MIA during embryogenesis with mouse models that are genetically deficient for Cntnap2 (604569), Fmr1 (309550), or Shank3 (606230). They established that the social behavior deficits in offspring exposed to MIA could be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioral rescue was accompanied by a reduction in neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which had been implicated by Shin Yim et al. (2017) in the manifestation of behavioral phenotypes associated with offspring exposed to MIA. By contrast, Reed et al. (2020) did not observe an LPS-induced rescue of social deficits in the monogenic models. Reed et al. (2020) demonstrated that the differences in responsiveness to the LPS treatment between the MIA and the monogenic models emerged from differences in the levels of cytokine production. LPS treatment in monogenic mutant mice did not induce amounts of Il17a (603149) comparable to those induced in MIA offspring; bypassing this difference by directly delivering Il17a into the S1DZ was sufficient to promote sociability in monogenic mutant mice as well as in MIA offspring. Conversely, abrogating the expression of Il17ra (605461) in the neurons of the S1DZ eliminated the ability of LPS to reverse the sociability phenotypes in MIA offspring. Reed et al. (2020) concluded that their data supported a neuroimmune mechanism that underlies neurodevelopmental disorders in which the production of Il17a during inflammation can ameliorate the expression of social behavior deficits by directly affecting neuronal activity in the central nervous system.


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  47. Tanaka, S., Jiang, Y., Martinez, G. J., Tanaka, K., Yan, X., Kurosaki, T., Kaartinen, V., Feng, X.-H., Tian, Q., Wang, X., Dong, C. Trim33 mediates the proinflammatory function of Th17 cells. J. Exp. Med. 215: 1853-1868, 2018. [PubMed: 29930104, images, related citations] [Full Text]

  48. Tong, Z., Liu, W., Yan, H., Dong, C. Interleukin-17A deficiency ameliorates streptozotocin-induced diabetes. Immunology 146: 339-346, 2015. [PubMed: 26211676, images, related citations] [Full Text]

  49. Torchinsky, M. B., Garaude, J., Martin, A. P., Blander, J. M. Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation. Nature 458: 78-82, 2009. [PubMed: 19262671, related citations] [Full Text]

  50. Toy, D., Kugler, D., Wolfson, M., Vanden Bos, T., Gurgel, J., Derry, J., Tocker, J., Peschon, J. Interleukin 17 signals through a heteromeric receptor complex. J. Immun. 177: 36-39, 2006. [PubMed: 16785495, related citations] [Full Text]

  51. Wang, X., Zhang, Y., Yang, X. O., Nurieva, R. I., Chang, S. H., Ojeda, S. S., Kang, H. S., Schluns, K. S., Gui, J., Jetten, A. M., Dong, C. Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity 36: 23-31, 2012. [PubMed: 22244845, images, related citations] [Full Text]

  52. Wynn, J. L., Wilson, C. S., Hawiger, J., Scumpia, P. O., Marshall, A. F., Liu, J.-H., Zharkikh, I., Wong, H. R., Lahni, P., Benjamin, J. T., Plosa, E. J., Weitkamp, J.-H., and 9 others. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18. Proc. Nat. Acad. Sci. 113: E2627-E2635, 2016. [PubMed: 27114524, images, related citations] [Full Text]

  53. Yao, Z., Painter, S. L., Fanslow, W. C., Ulrich, D., Macduff, B. M., Spriggs, M. K., Armitage, R. J. Human IL-17: a novel cytokine derived from T cells. J. Immun. 155: 5483-5486, 1995. [PubMed: 7499828, related citations]

  54. Zielinski, C. E., Mele, F., Aschenbrenner, D., Jarrossay, D., Ronchi, F., Gattorno, M., Monticelli, S., Lanzavecchia, A., Sallusto, F. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1-beta. Nature 484: 514-518, 2012. [PubMed: 22466287, related citations] [Full Text]


Ada Hamosh - updated : 06/09/2020
Bao Lige - updated : 10/25/2018
Paul J. Converse - updated : 01/03/2018
Paul J. Converse - updated : 07/28/2016
Paul J. Converse - updated : 06/06/2016
Paul J. Converse - updated : 3/3/2016
Paul J. Converse - updated : 2/4/2016
Ada Hamosh - updated : 10/13/2015
Paul J. Converse - updated : 7/10/2015
Paul J. Converse - updated : 7/8/2015
Paul J. Converse - updated : 4/29/2015
Paul J. Converse - updated : 3/19/2015
Ada Hamosh - updated : 3/12/2015
Paul J. Converse - updated : 1/28/2015
Paul J. Converse - updated : 8/19/2013
Paul J. Converse - updated : 3/12/2013
Ada Hamosh - updated : 12/4/2012
Patricia A. Hartz - updated : 9/21/2012
Paul J. Converse - updated : 6/4/2012
Ada Hamosh - updated : 5/4/2012
Paul J. Converse - updated : 3/8/2012
Paul J. Converse - updated : 2/13/2012
Paul J. Converse - updated : 8/5/2011
Paul J. Converse - updated : 8/5/2011
Paul J. Converse - updated : 4/28/2011
Paul J. Converse - updated : 3/25/2011
Paul J. Converse - updated : 1/24/2011
Paul J. Converse - updated : 7/29/2010
Paul J. Converse - updated : 5/28/2009
Ada Hamosh - updated : 4/2/2009
Paul J. Converse - updated : 11/18/2008
Paul J. Converse - updated : 11/13/2008
Ada Hamosh - updated : 5/21/2008
Paul J. Converse - updated : 3/5/2008
Paul J. Converse - updated : 11/2/2007
Ada Hamosh - updated : 9/11/2007
Paul J. Converse - updated : 7/2/2007
Paul J. Converse - updated : 4/12/2007
Paul J. Converse - updated : 4/4/2007
Paul J. Converse - updated : 8/29/2006
Paul J. Converse - updated : 7/6/2006
Paul J. Converse - updated : 6/23/2006
Paul J. Converse - updated : 5/5/2006
Paul J. Converse - updated : 1/12/2006
Marla J. F. O'Neill - updated : 2/18/2005
Victor A. McKusick - updated : 6/19/2003
Victor A. McKusick - updated : 5/20/1999
Creation Date:
Jennifer P. Macke : 10/15/1998
alopez : 04/05/2023
alopez : 06/09/2020
carol : 03/27/2019
mgross : 10/25/2018
mgross : 01/03/2018
mgross : 07/28/2016
mgross : 06/06/2016
mgross : 3/3/2016
mgross : 2/4/2016
alopez : 10/13/2015
mgross : 8/12/2015
mgross : 7/24/2015
mgross : 7/24/2015
mgross : 7/24/2015
mcolton : 7/17/2015
mcolton : 7/10/2015
mcolton : 7/8/2015
mgross : 5/7/2015
mcolton : 4/29/2015
mgross : 3/25/2015
mcolton : 3/19/2015
alopez : 3/12/2015
mgross : 1/30/2015
mcolton : 1/28/2015
mgross : 8/19/2013
mgross : 3/19/2013
mgross : 3/19/2013
terry : 3/12/2013
carol : 12/21/2012
alopez : 12/6/2012
terry : 12/4/2012
terry : 9/27/2012
mgross : 9/26/2012
terry : 9/21/2012
mgross : 6/12/2012
mgross : 6/12/2012
terry : 6/4/2012
alopez : 5/7/2012
terry : 5/4/2012
mgross : 3/9/2012
terry : 3/8/2012
mgross : 2/16/2012
terry : 2/13/2012
mgross : 12/16/2011
mgross : 8/9/2011
mgross : 8/9/2011
terry : 8/5/2011
terry : 8/5/2011
alopez : 5/4/2011
mgross : 5/3/2011
terry : 4/28/2011
terry : 3/25/2011
mgross : 3/8/2011
terry : 3/7/2011
mgross : 2/2/2011
terry : 1/24/2011
mgross : 8/19/2010
terry : 7/29/2010
carol : 5/25/2010
carol : 4/5/2010
carol : 12/23/2009
mgross : 12/7/2009
terry : 11/25/2009
mgross : 10/29/2009
terry : 10/27/2009
mgross : 5/29/2009
terry : 5/28/2009
mgross : 4/30/2009
terry : 4/23/2009
alopez : 4/3/2009
terry : 4/2/2009
mgross : 11/19/2008
terry : 11/18/2008
mgross : 11/17/2008
terry : 11/13/2008
alopez : 5/28/2008
terry : 5/21/2008
mgross : 3/5/2008
mgross : 11/2/2007
alopez : 9/11/2007
mgross : 8/21/2007
terry : 7/2/2007
mgross : 4/12/2007
mgross : 4/12/2007
terry : 4/12/2007
mgross : 4/11/2007
mgross : 4/5/2007
mgross : 4/5/2007
terry : 4/4/2007
mgross : 12/6/2006
mgross : 8/29/2006
mgross : 7/6/2006
mgross : 6/23/2006
mgross : 5/8/2006
mgross : 5/8/2006
terry : 5/5/2006
mgross : 1/12/2006
terry : 4/5/2005
wwang : 2/23/2005
terry : 2/18/2005
alopez : 6/25/2003
terry : 6/19/2003
mgross : 12/7/2000
mgross : 6/4/1999
mgross : 5/28/1999
terry : 5/20/1999
terry : 11/19/1998
alopez : 10/15/1998

* 603149

INTERLEUKIN 17A; IL17A


Alternative titles; symbols

IL17
CYTOTOXIC T-LYMPHOCYTE-ASSOCIATED SERINE ESTERASE 8; CTLA8


HGNC Approved Gene Symbol: IL17A

Cytogenetic location: 6p12.2     Genomic coordinates (GRCh38): 6:52,186,375-52,190,638 (from NCBI)


TEXT

Description

IL17 is a proinflammatory cytokine that is secreted primarily by activated T cells and that has been implicated in several important inflammatory human diseases. IL17 stimulates a variety of cells to produce inflammatory mediators including IL1 (see 147760), TNFA (191160), and chemokines. These events ultimately lead to the recruitment of neutrophils and other leukocytes that is the hallmark of inflammatory disease (summary by Lopez Kostka et al., 2009).


Cloning and Expression

Rouvier et al. (1993) used subtractive library screening to isolate a novel rodent gene, termed CTLA8, that was expressed specifically in cytotoxic T cells. Although Rouvier et al. (1993) described CTLA8 as a mouse gene, Kennedy et al. (1996) showed that it is actually the rat IL17 homolog. Rouvier et al. (1993) noted that the CTLA8 polypeptide sequence is 56.8% identical to that of the immediate-early gene 13 of Herpesvirus saimiri (HVS-13). The CTLA8 3-prime untranslated region contains AU-rich repeats typically found in the mRNA of cytokines and growth factors.

Yao et al. (1995) cloned a human IL17 cDNA. The cDNA encodes a 155-amino acid polypeptide that contains an N-terminal hydrophobic signal sequence. Northern blot analysis revealed that the gene is expressed as a 1.9-kb mRNA in stimulated, but not resting, T cells; the transcript could not be detected in any human tissues. Expressed recombinant IL17 was secreted in both glycosylated and nonglycosylated forms. IL17 protein applied to fibroblasts induced the production of IL6 (147620) and IL8 (146930) and enhanced surface expression of intracellular adhesion molecule-1 (ICAM1; 147840).


Gene Function

Using a mouse coculture system, Kotake et al. (1999) examined the potential role of IL17 in osteoclastogenesis. Treatment of cocultures of mouse hematopoietic cells and primary osteoblasts with recombinant human IL17 induced the formation of multinucleated cells that satisfied major criteria of osteoblasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentin slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin, a selective inhibitor of cyclooxygenase-2 (COX2; 600262). The addition of IL17 increased prostaglandin E2 (PGE2) synthesis in the cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL17 dose-dependently induced expression of osteoclast differentiation factor (ODF; 602642) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF; 602643), a decoy receptor of ODF, completely inhibited IL17-induced osteoclast differentiation in the cocultures.

Kotake et al. (1999) found that levels of IL17 in synovial fluids were significantly higher in rheumatoid arthritis (RA; 180300) patients than in osteoarthritis (165720) patients. Anti-IL17 antibodies significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggested that IL17 first acts on osteoblasts, which stimulates both COX2-dependent PGE2 synthesis and ODF gene expression, which in turn induces differentiation of osteoclast progenitors into mature osteoclasts, and that IL17 is a crucial cytokine for osteoclastic bone resorption in RA patients.

Although there are elevated levels of IL17 in synovial fluid of patients with rheumatoid arthritis, its pathogenic role in that disease remained to be elucidated. Nakae et al. (2003) examined the effects of IL17 deficiency in mice deficient for the IL1 receptor antagonist (IL1Ra -/-; 147679), which spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL1 signaling. IL17 expression is greatly enhanced in these mice, suggesting that IL17 activity is involved in the pathogenesis of the arthritis in these mice. Indeed, Nakae et al. (2003) found that the spontaneous development of arthritis did not occur in IL1 Ra -/- mice also deficient in IL17. Crosslinking OX40 (600315), a cosignaling molecule on CD4+ T cells that plays an important role in T cell antigen-presenting cell interaction, with anti-OX40 antibody accelerated the production of IL17 induced by CD3 stimulation. Because OX40 is induced by IL1 signaling, IL17 induction was thought to be downstream of IL1 through activation of OX40. These observations suggested the IL17 plays a crucial role in T cell activation, downstream of IL1, causing the development of autoimmune arthritis.

Using immunohistochemistry, McAllister et al. (2005) localized IL17R (IL17RA; 605461) to basal airway cells in lung tissue. Both IL17 and IL17F (606496), in synergy with TNF (191160), upregulated GCSF (CSF3; 138970) and GROA (CXCL1; 155730) expression in bronchial epithelial cells in a time-dependent manner via the basolateral, rather than the apical, surfaces of the cells. This upregulation was inhibited by anti-IL17R, but only IL17 was inhibited by soluble IL17R. Immunohistochemical and functional analyses demonstrated basolateral expression of TNFR1 (TNFRSF1A; 191190) and TNFR2 (TNFRSF1B; 191191). During episodes of pulmonary exacerbation, cystic fibrosis (CF; 219700) patients showed increased IL23 (see 605580), IL17, and IL17F expression, and these levels decreased with antibiotic treatment. McAllister et al. (2005) proposed that targeting IL17 and IL17F or antagonizing IL17R might mitigate neutrophil-mediated inflammation in CF.

Harrington et al. (2005) showed that development of the proinflammatory subset of Il17-secreting T helper cells, which they called Th17 cells, occurred optimally in the presence of Il23 (see IL23A; 605580) in mice, whereas Th1 and Th2 cells responded poorly to Il23. Ifng (147570) and Il4 (147780), inducers of Th1 and Th2 development, respectively, suppressed development of Th17 cells, which were instead derived from naive precursor cells. Type I interferons (e.g., IFNA1; 147660) also inhibited Th17 development. Th17 development was undiminished, and in some cases enhanced, in mouse cells lacking Stat1 (600555), Stat4 (600558), or Tbet (TBX21; 604895), which are necessary for Th1 development, and in cells lacking Stat6 (601512), which is necessary for Th2 development, Differentiated Th17 effector cells were relatively resistant to inhibition by Il4 or Ifng. Harrington et al. (2005) concluded that inhibition of IFNG signaling enhances development of pathogenic Th17 effector cells that exacerbate autoimmunity.

Park et al. (2005) reported findings similar to those of Harrington et al. (2005), but they observed a more potent inhibition of Il23-dependent Il17 production by Il4. In addition, Park et al. (2005) showed that generation of Il17-producing Th cells in mice required costimulation by Cd28 (186760) and Icos. Mice overexpressing Il17 in lung epithelial cells experienced substantial pulmonary pathology accompanied by production of multiple chemokines. Treatment with neutralizing anti-Il17 before or after onset of experimental autoimmune encephalomyelitis inhibited chemokine expression and prevented development of disease. Park et al. (2005) concluded that IL17 is expressed by a novel subset of Th cells and is crucial in regulating tissue inflammatory reactions.

Mangan et al. (2006) showed that exogenous Tgfb (190180) induced development of Th17 cells in Il12b (161561) -/- mice, whose antigen-presenting cells produce neither Il12 or Il23. In Ifng -/- T cells, Tgfb induced expression of Il23r (607562), conferring Il23 responsiveness for Th17 cell development. Challenge of Il12b -/- mice or Il23a -/- mice with a natural rodent pathogen, Citrobacter rodentium, resulted in failure to clear infection and death. In contrast to Il12b -/- mice, Il23a -/- mice did not show impaired induction of an Il17 response. Histopathologic and flow cytometric analysis demonstrated that intestinal tissue was enriched in Th17 cells in wildtype mice, but not in Tgfb -/- mice; Tgfb +/- mice had intermediate levels of Th17 cells. Activation of naive T cells with Tgfb resulted in expression of both intracellular Il17 and Foxp3 (300292), a transcription factor associated with regulatory T cells (Treg cells). Addition of Il6, however, nearly extinguished the Foxp3-positive cells. Mangan et al. (2006) concluded that TGFB plays a dual role in T-cell differentiation by directing distinct populations of FOXP3-positive Treg cells and Th17 cells, contingent upon the inflammatory cytokine environment.

Using flow cytometric, ELISA, immunoprecipitation, and Western blot analyses, Toy et al. (2006) showed that expression of both human IL17RA and IL17RC (610925) on Il17ra-deficient mouse fibroblasts was necessary for either human IL17 or IL17F to fully bind cells and induce secretion of CXCL1. Immunoprecipitation analysis revealed a physical association between IL17RA and IL17RC. Toy et al. (2006) concluded that the functional IL17R is a heteromeric complex consisting of at least IL17RA and IL17RC.

Tan et al. (2006) noted that mice lacking Il17ra have reduced resistance to bacterial and fungal infections. They found that Il17ra -/- mice had normal baseline hematopoiesis, but they were more susceptible to hematopoietic toxicity from gamma irradiation and succumbed at lower levels of radiation than wildtype mice. Neutrophils decreased in a dose-dependent fashion after x-ray treatment. Infusion of Cd4 (186940)-positive T cells following irradiation enhanced hematopoietic recovery in wildtype mice, but not in Il17ra -/- mice or mice treated with anti-Il17ra. Overexpression of Il17a in normal mice also enhanced granulopoiesis following irradiation. Tan et al. (2006) concluded that IL17A is required for recovery of granulopoiesis after radiation injury.

Amadi-Obi et al. (2007) found that Th17 cells were present in human uveitis, as well as in mouse experimental autoimmune uveoretinitis (EAU). Flow cytometric analysis demonstrated that Th17 cell numbers increased during active uveitis and, in peripheral blood cells, were expanded by IL2 (147680) and inhibited by IFNG. Anti-IL17 ameliorated EAU in mice, and IL27 inhibited uveitogenic T cells in an Ifng- and Stat1-dependent manner. Amadi-Obi et al. (2007) proposed that Th1 cells may mitigate uveitis by antagonizing Th17 cells through IFNG, suggesting that antagonism of Th17 by IFNG and/or IL27 may be useful for treatment of chronic inflammation.

Steinman (2007) reviewed the Th17 hypothesis of cell-mediated tissue damage and the paradigm shift from the Th1/Th2 hypothesis developed in the 1980s.

TGF-beta converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of IL6 (147620), TGF-beta also promotes the differentiation of naive T lymphocytes into proinflammatory IL17 cytokine-producing Th17 cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. Mucida et al. (2007) identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL6-driven induction of proinflammatory Th17 cells and promoting antiinflammatory Treg differentiation. Mucida et al. (2007) concluded that a common metabolite can regulate the balance between pro- and antiinflammatory immunity.

Using an in vitro model of the human blood-brain barrier (BBB) with brain-derived microvascular endothelial cells, Kebir et al. (2007) demonstrated that IL17 and IL22 (605330) disrupted BBB tight junctions in vitro. CD45RO (151460)-positive cells expressing IL17 and IL22 were present in multiple sclerosis (MS; see 126200) lesions, and IL17R and IL22R (see 605457) were expressed on BBB endothelial cells in MS lesions, but not control brain material. Th17 lymphocytes transmigrated efficiently across BBB endothelial cells, expressed high levels of granzyme B (GZMB; 123910), killed human neurons, and promoted central nervous system inflammation through CD4-positive lymphocyte recruitment.

Using flow cytometry and ELISA, Sato et al. (2007) found that CCR2 (601267)-positive, but not CCR2-negative, CD4-positive T cells produced IL17. Within the CCR2-positive population, CCR5 (601373)-positive cells produced IFNG and CCR5-negative cells produced IL17. Sato et al. (2007) concluded that human Th17 cells are CCR2-positive/CCR5-negative.

Coury et al. (2008) detected high levels of soluble RANKL (TNFSF11; 602642) and IL17A, but not IL1B (147720), IL22, or TNF, in serum from patients with Langerhans cell histiocytosis (LCH; 604856). Immunohistochemical analysis demonstrated IL17A-positive dendritic cells (DCs) in LCH patient skin and bone lesions and in multinucleated giant cells (MGCs). Intracytoplasmic flow cytometry and ELISA identified DCs, and not T cells, as the source of IL17A in LCH. IL17A stimulation induced fusion of healthy DCs in vitro. LCH DCs behaved similarly to IL17A-stimulated healthy DCs, and transwell assays confirmed that IL17A secreted from LCH DCs was functional. Gene chip analysis showed that IL17A was responsible for expression of TRAP (ACP5; 171640), MMP9 (120361), and MMP12 (601046) by MGCs in healthy DCs. Healthy DCs treated with IL17A and LCH DCs and MGCs displayed overactivation of TRAP. IgG autoantibody to IL17A was also detected in LCH serum. Coury et al. (2008) proposed that IL17A has a major role in LCH severity and may be a therapeutic target in the disease. They also suggested that DCs may be effector cells in other IL17A-related diseases.

In a follow-up study to Coury et al. (2008), Allen and McClain (2009) reported that they were unable to detect IL17A mRNA by RT-PCR in CD207 (604862)-positive Langerhans cells or CD3-positive T cells isolated by flow cytometry from 14 LCH biopsy samples. In addition, they could not detect significant levels of serum IL17A in LCH patients. In response, Arico et al. (2009) pointed out that they (i.e., Coury et al. (2008)) had detected IL17A in CD207-negative DCs, the majority cell population in LCH lesions, using different sets of antibodies from those used by Allen and McClain (2009). They also stated that their serum ELISA assay used a capture antibody able to outcompete autoantibodies to IL17A that are present in LCH sera. Both studies showed that serum IL17A concentrations did not correlate with LCH activity and that Th17 cells were not present in LCH lesions. Indirectly, there may also be concurrence between the studies in the statement by Arico et al. (2009) that LCH is a DC-related disease rather than a Langerhans cell-related disease.

Milner et al. (2008) showed that interleukin IL17 production by T cells is absent in individuals with hyper-IgE syndrome (HIES; 147060). They observed that ex vivo T cells from subjects with HIES failed to produce IL17, but not IL2 (147680), TNF (191160), or IFNG (147570), on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL17-producing (TH17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gamma-t (602943), which is consistent with a crucial role for STAT3 (102582) signaling in the generation of TH17 cells. TH17 cells are an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial infections. Thus, Milner et al. (2008) concluded that the inability to produce TH17 cells is a mechanism underlying the susceptibility to recurrent infections commonly seen in HIES.

Atarashi et al. (2008) found that cells expressing Il17, Rorc, and Il17f constituted a large proportion of Cd4-positive T cells in the intestinal lamina propria of mice. These 'naturally occurring' Th17 cells were selectively and constitutively present, even under specific-pathogen-free conditions, and their numbers increased with age. Flow cytometric analysis showed that Th17 numbers were reduced in the lamina propria of germ-free mice, but ATP, derived from commensal bacteria or administered systemically or rectally, caused an increase in lamina propria Th17 cells that was mediated by Cd70 (TNFSF7; 602840)-high/Cd11c (ITGAX; 151510)-low myeloid cells expressing P2x (e.g., P2RX2; 600844) and P2y (e.g., P2RY6; 602451) receptors, as well as Il6, Il23p19, Itgav (193210), and Itgb8 (604160). Furthermore, administration of ATP exacerbated a T cell-mediated colitis model with enhanced Th17 differentiation. Atarashi et al. (2008) concluded that commensal bacteria and ATP are important for Th17 differentiation in health and disease, and that they may explain why Th17 cells are present specifically in the intestinal lamina propria.

Torchinsky et al. (2009) demonstrated that the physiologic stimulus necessary to trigger a Th17 response is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL6 and transforming growth factor-beta (190180) through recognition of pathogen-associated molecular patterns and phosphatidylserine exposed on apoptotic cells, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium, which models human infections with the attaching and effacing enteropathogenic and enterohemorrhagic E. coli, impairs the characteristic Th17 response in the lamina propria. Torchinsky et al. (2009) concluded that their results demonstrated that infected apoptotic cells are a critical component of the innate immune signals instructing Th17 differentiation, and pointed to pathogens particularly adept at triggering apoptosis that might preferentially induce Th17-mediated immunity. Torchinsky et al. (2009) proposed that because Th17 cells have been correlated with autoimmune diseases, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.

Using predominantly wildtype and Hif1a (603348) -/- mouse T cells, Dang et al. (2011) showed that Hif1a was specifically required for differentiation of naive T cells into Th17 cells. Hif1a interacted directly with Ror-gamma-t and acetyltransferase p300 (EP300; 602700) at the Il17 promoter, and all 3 factors were required for optimum Il17 expression. Simultaneously, Hif1a downregulated differentiation of naive T cells into Treg cells by directing proteasomal degradation of Foxp3 by a mechanism that was independent of Hif1a transcriptional activity. Differentiation of Th17 cells and loss of Treg cells was enhanced in cultures subjected to hypoxic conditions. Knockout of Hif1a in mouse T cells rendered mice highly resistant to Mog (159465)-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Dang et al. (2011) concluded that HIF1A has a role in immune responses by controlling the balance between Th17 and Treg cells.

Using Lxra (NR1H3; 602423) and Lxrb (NR1H2; 600380) double-knockout mice and Lxr agonists, Cui et al. (2011) observed Lxr-dependent amelioration of experimental autoimmune encephalomyelitis. Lxr overexpression decreased, whereas Lxr deficiency promoted, cytokine-driven mouse Th17 cell differentiation and polarization in vitro. In mouse, Srebp1 (SREBF1; 184756) was recruited to the E-box element on the Il17 promoter upon Lxr activation and interacted with Ahr (600253) to inhibit Il17 transcriptional activity. LXR activation in human cells also suppressed Th17 cell differentiation, promoted SREBP1 expression, and decreased AHR expression. Mutation and coimmunoprecipitation analyses showed that the putative active-site domain of mouse Ahr and the N-terminal acidic region of mouse Srebp1 were essential for Ahr-Srebp1 interaction. Cui et al. (2011) concluded that a downstream target of LXR, SREBP1, antagonizes AHR to suppress Th17 cell generation and autoimmunity.

Using an approach that combined the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, Zielinski et al. (2012) described 2 types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL17 and IFN-gamma but no IL10 (124092), whereas Staphylococcus aureus-specific TH17 cells produced IL17 and could produce IL10 upon restimulation. IL6 (147620), IL23 (see 605580), and IL1-beta (147720) contributed to TH17 differentiation induced by both pathogens, but IL1-beta was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL12 (see 161561) and to prime IL17/IFN-gamma double-producing cells. In addition, IL1-beta inhibited IL10 production in differentiating and in memory TH17 cells, whereas blockade of IL1-beta in vivo led to increased IL10 production by memory TH17 cells. Zielinski et al. (2012) showed that, after restimulation, TH17 cells transiently downregulated IL17 production through a mechanism that involved IL2 (147680)-induced activation of STAT5 (601511) and decreased expression of ROR-gamma-t. Zielinski et al. (2012) concluded that, taken together, their findings demonstrated that by eliciting different cytokines, C. albicans and S. aureus prime TH17 cells that produce either IFN-gamma or IL10, and identified IL1-beta and IL2 as pro- and antiinflammatory regulators of TH17 cells both at priming and in the effector phase.

Grivennikov et al. (2012) investigated mechanisms responsible for tumor-elicited inflammation in a mouse model of colorectal tumorigenesis which, like human colorectal cancer, exhibits upregulation of IL23 and IL17. They showed that IL23 signaling promotes tumor growth and progression, and development of tumoral IL17 response. IL23 is mainly produced by tumor-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumors but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. Grivennikov et al. (2012) proposed that barrier deterioration induced by colorectal cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumor-elicited inflammation, which in turn drives tumor growth.

Santarlasci et al. (2012) noted that Th17 cells have a critical pathogenic role in chronic inflammatory disorders, but they are rarely found in inflammatory sites. Santarlasci et al. (2012) found that, unlike Th1 cells, human CD161 (KLRB1; 602890)-positive Th17 precursor cells did not proliferate and produce IL2 in response to anti-CD3/anti-CD28 stimulation. Th17 cells also proliferated poorly in response to IL2, in part due to lower expression of the transcription factors JUN (165160), FOS (164810), and NFATC1 (600489) and reduced surface expression of CD3E (186830) and CD3Z (CD247; 186780). Microarray and small interfering RNA analyses revealed high expression of IL4I1 (609472) in Th17 precursor cells and showed that IL4I1 upregulation was strictly dependent on RORC (602943), the Th17 master regulatory gene. Flow cytometric analysis revealed that Th17 cells also exhibited high CD28 expression that was RORC dependent, and stimulation of CD28 alone induced IL17 production and IL4I1 mRNA upregulation. Th17 cells from synovial fluid of patients with juvenile idiopathic arthritis (see 604302) also expressed higher levels of IL4I1 and CD28 than did Th1 cells. Santarlasci et al. (2012) concluded that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms that limit their expansion and, therefore, reduce their potential to cause damage.

By stimulating T cells from mice with a conditional knockout of Egr2 (129010), Miao et al. (2013) observed high induction of Il1, Il17, and Il21 (605384), but not Il2 or Ifng. Egr2, but not other EGR genes, was induced in naive mouse T cells by the Th17-cell inducers Tgfb and Il6, but not by Ifng or Il4, which promote Th1 and Th2 cells, respectively. Although expression of Th17 regulatory factors was not affected in Egr2-deficient Th17 cells, binding of Batf (612476) to DNA-binding sites in the Il17 promoters was significantly increased in Egr2-deficient Th17 cells. Mice lacking Egr2 were susceptible to induction of experimental autoimmune encephalomyelitis. Stimulated CD4 T cells from patients with multiple sclerosis showed normal expression of BATF, significantly reduced expression of EGR2, and increased expression of IL17. Miao et al. (2013) concluded that EGR2 is involved in regulation of Th17 cytokine production and Th17 differentiation by inhibiting BATF function and that EGR2 is important in the control of autoimmunity and inflammation.

Ling et al. (2013) found that treatment of a mouse macrophage cell line with Il17a prior to infection with the avirulent M. bovis BCG vaccine strain enhanced BCG-induced nitric oxide (NO) production and inducible NO synthase (NOS2A; 163730) expression in a dose- and time-dependent manner. The effect was not observed in human monocyte-derived macrophages. The synergism in mouse macrophages appeared to be mediated by enhanced BCG-induced phosphorylation of Jnk (MAPK8; 601158), but not of Erk1 (MAPK3; 601795), Erk2 (MAPK1; 176948), or p38 (MAPK14; 600289). Treatment with a Jnk inhibitor suppressed NO production in BCG-treated macrophages. Ling et al. (2013) concluded that the Jnk pathway is involved in Il17a-enhanced NO production in BCG-infected mouse macrophages and that Il17a enhances the clearance of BCG by macrophages through an NO-dependent killing mechanism.

By RT-PCR and flow cytometric analyses, Gosmann et al. (2014) detected elevated expression of IL17 and IL23 in human precancerous cervical intraepithelial neoplasia (CIN) compared with control cervical tissue. Expression of Il17 and Il23 was also elevated in the skin of transgenic mice expressing the human papillomavirus (HPV) protein E7 compared with control mouse skin. Transplant of E7 transgenic skin from mice lacking Il17, but not from mice heterozygous for Il17, resulted in rejection by controls. CD4-positive T cells were the predominant source of IL17 in human CIN, and CD4-positive and gamma/delta T cells were the predominant sources of Il17 in transgenic mouse skin. Production of Il17 was induced by Il23 and Il1b, but not by Il18 (600953), in E7 transgenic skin. Gosmann et al. (2014) concluded that IL17 mediates immunosuppression in HPV-associated epithelial neoplasia. They proposed that IL17 blockade may be of therapeutic use in persistent infection with high-risk HPV strains and may prevent progression to malignant lesions.

Kshirsagar et al. (2014) reported that enhanced STAT3 activity in CD4-positive/CD45A (see 151460)-negative/FOXP3-negative and FOXP3-low effector T cells from children with lupus nephritis (LN; see 152700) correlated with increased frequency of IL17-producing cells within these T-cell populations. Rapamycin treatment reduced both STAT3 activation and Th17 cell frequency in lupus patients. Th17 cells from children with LN exhibited high AKT (164730) activity and enhanced migratory capacity. Inhibition of AKT in cells from LN patients resulted in reduced Th17-cell migration. Kshirsagar et al. (2014) concluded that the AKT signaling pathway plays a significant role in Th17-cell migratory activity in children with LN. They suggested that inhibition of AKT may result in suppression of chronic inflammation in LN.

Erbel et al. (2014) found that treatment of mature Apoe (107741)-null mice for 6 weeks with anti-Il17a prevented atherosclerotic lesion progression and improved lesion stability via reduction in inflammatory burden and cellular infiltration. Experiments in vitro showed that IL17A played a role in chemoattraction, monocyte adhesion, and antigen-presenting cell sensitization toward pathogen-derived TLR4 (603030) ligands. Stimulation of human carotid plaque tissue ex vivo with IL17A induced a proinflammatory milieu. Erbel et al. (2014) concluded that IL17A is an important proatherogenic cytokine that may be an attractive therapeutic target for preventing atherosclerotic lesion progression.

Rutz et al. (2015) showed that the deubiquitylating enzyme DUBA (OTUD5; 300713) is a negative regulator of IL17A production in T cells. Mice with Duba-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. Duba interacted with the ubiquitin ligase Ubr5 (608413), which suppressed Duba abundance in naive T cells. Duba accumulated in activated T cells and stabilized Ubr5, which then ubiquitylated ROR-gamma-t in response to TGFB (190180) signaling. Rutz et al. (2015) concluded that their data identified DUBA as a cell-intrinsic suppressor of IL17 production.

Using mouse models of spontaneous breast cancer metastasis, Coffelt et al. (2015) demonstrated that breast tumors maximize their chance of metastasizing by invoking a systemic inflammatory cascade. Coffelt et al. (2015) mechanistically demonstrated that IL1B (147720) elicits IL17 expression from gamma-delta T cells, resulting in systemic granulocyte colony-stimulating factor (GCSF; 138970)-dependent expansion and polarization of neutrophils in mice bearing mammary tumors. Tumor-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen (see 186730), which limit the establishment of metastases. Neutralization of IL17 or GCSF and absence of gamma-delta T cells prevents neutrophil accumulation and downregulates the T cell-suppressive phenotype of neutrophils. Moreover, the absence of gamma-delta T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumor progression. Coffelt et al. (2015) concluded that targeting this novel cancer cell-initiated domino effect within the immune system--the gamma-delta T cell/IL17/neutrophil axis--represents a novel strategy to inhibit metastatic disease.

Using single-cell RNA sequencing analysis of mouse Th17 cells differentiated in vitro under pathogenic versus nonpathogenic conditions or of Th17 cells isolated ex vivo from lymph nodes or central nervous system of mice undergoing experimental autoimmune encephalomyelitis (EAE), Kishi et al. (2016) showed that expression of Procr (600646) correlated inversely with Th17-cell pathogenicity. Procr expression was regulated by transcription factors critical for Th17 differentiation, including Stat3, Irf4 (601900), and Rorgt. Procr overexpression reduced expression of the Th17 proinflammatory module, including Il1r (IL1R1; 147810) and Il23r (607562). Using different EAE mouse models, Kishi et al. (2016) found that loss or reduction of Procr expression led to increased Th17 pathogenicity and enhanced EAE in vivo. Kishi et al. (2016) concluded that PROCR is a negative regulator of Th17 pathogenicity.

Tanaka et al. (2018) showed that conditional knockout of Trim33 (605769) in T cells of mice resulted in decreased Il17 and Ccr6 (601835) expression, but enhanced Il10 production, leading to protection against EAE. Further examination revealed that Trim33 played a crucial role in differentiation of Th17 cells, but not inducible Treg cells. Microarray and real-time RT-PCR analyses confirmed downregulation of Il17 and Ccr6 and upregulation of Il10 in the absence of Trim33. Il17 and Ccr6 downregulation was not due to enhanced Il10 expression, as Il10 blockade did not restore Il17 and Ccr6 expression in Trim33-knockout T cells. Genomewide analysis of Trim33-bound genes showed that Il17 and Il10 were collaboratively regulated by Trim33 and Ror-gamma at the transcriptional level. Trim33 controlled Il17 and Il10 expression at the chromatin level through regulation of histone modifications. Smad2 (601366) was crucial for binding of Trim33 to Il17 and Il10 loci, and the Trim33/Smad2/Ror-gamma complex was necessary for optimal expression of Il17 and repression of Il10 in Th17 cells. Moreover, enhanced expression of Il10 in Trim33-knockout T cells was almost completely suppressed by deletion of Smad4 (600993), indicating that Trim33 suppresses Il10 expression by reduction of Smad4 protein in T cells. The authors concluded that TRIM33 promotes the proinflammatory function of Th17 cells by inducing IL17 and suppressing IL10 expression.


Mapping

Rouvier et al. (1993) used in situ hybridization to map the IL17 gene to human chromosome 2q31 and to mouse chromosome 1A, in a region of known syntenic homology.


Animal Model

Nakae et al. (2002) tested various disease models in Il17-deficient mice and found that Il17 was involved in contact, delayed, and airway hypersensitivity, but not in acute graft-versus-host reaction (see 614395). They proposed that IL17 plays an important role in allergen-specific T cell-mediated immune responses.

Nakae et al. (2003) found that collagen-induced arthritis was markedly reduced in mice lacking Il17. They showed that Il17 was necessary for priming of collagen-specific T cells and IgG2a production.

Using a murine model of acute fatal pneumonia, Priebe et al. (2008) showed that use of an attenuated Pseudomonas aeruginosa strain as a vaccine mediated protection not only against the parental strain, but also against other cytotoxic variants. However, serum from the vaccinated mice had low levels of opsonic antibody but high levels of neutrophils after challenge, and their T cells produced high levels of Il17. Mice lacking Il17r were not protected from virulent challenge. Priebe et al. (2008) concluded that IL17 plays a critical role in antibody-independent vaccine-induced protection against P. aeruginosa in lung.

Lin et al. (2009) noted that IFNG and Th1 immunity are critical for host resistance to the intracellular bacterium Francisella tularensis, the causative agent of tularemia and a potential bioterrorism agent. Using mice lacking various cytokines and ELISPOT analysis, they demonstrated that Il23-dependent Il17a was induced during F. tularensis infection and was required for induction of Il12, optimal induction of Th1 cell responses, and host resistance to infection. Lin et al. (2009) concluded that IL17A, but not IL17F or IL22, functions to regulate IL12-Th1 cell immunity and host responses to an intracellular pathogen.

Lopez Kostka et al. (2009) noted that C57BL/6 mice develop Th1/Tc1 cell-dependent resistance to cutaneous leishmaniasis, whereas BALB/c mice preferentially develop Th2 immunity and succumb to infection. They found that neutrophils and Cd4-positive T cells from BALB/c mice produced increased amounts of Il17 during Leishmania major infection compared with cells from C57BL/6 mice. Correspondingly, BALB/c DCs produced more Il23 than C57BL/6 DCs after L. major infection, whereas Il6 and Tgfb production was comparable in BALB/c and C57BL/6 DCs. Infected Il17 -/- BALB/c mice had smaller, nonprogressing lesions compared with control mice. Amounts of Il4, Il10 (124092), and Ifng produced by T cells were comparable in Il17 -/- and wildtype BALB/c mice. The improved disease outcome was associated with decreased Cxcl2 (139110) accumulation in lesion sites and decreased neutrophil migration into lesions of Il17 -/- mice. Lopez Kostka et al. (2009) proposed that IL23 production by L. major-infected DCs maintains IL17-positive cells that influence disease progression via regulation of neutrophil recruitment.

Kagami et al. (2010) observed delayed healing and decreased Il17a production following skin infection with Candida albicans in mice lacking Il23 or Il17a compared with wildtype mice or mice lacking Il12 or Il22. Histologic analysis revealed epidermal hyperplasia overlying infected dermis in wildtype mice, but fungal burden was greater and epidermal hyperplasia was severely reduced in Il23 -/- mice. Il23 -/- mice also failed to express Il17a or Il22 mRNA. Injection of recombinant Il17a promoted rapid healing in wildtype mice and mice lacking Il23 or Il12. Kagami et al. (2010) concluded that IL23 and IL17A, but not IL12 or IL22, are required for optimal host defense against cutaneous candidiasis. They also proposed that cutaneous candidiasis may be treatable with recombinant IL17A.

By flow cytometric analysis, Mayuzumi et al. (2010) found constitutive Il17a production in mouse lamina propria, Peyer patch, and mediastinal lymph node, but not in intraepithelial T lymphocytes. Ifng production was induced by Salmonella enterica (Typhimurium) infection in gut-associated lymphoid tissue. Neutralization of Il17 suppressed induction of the antimicrobial peptide, beta-defensin-3 (DEFB103A; 606611) at the site of the intestinal mucosa. Mayuzumi et al. (2010) proposed that IL17 participates in the immediate-early stage of protection against S. typhimurium intestinal infection, whereas IFNG is important at later stages of infection.

Geddes et al. (2011) infected mice with Citrobacter rodentium or Salmonella typhimurium species and observed triggering of early Il17 production that was crucial for host defense mediated by Cd4-positive helper T cells. Th17 responses occurred principally in the cecum and were mediated by innate Th17 cells that were regulated by Nod1 (605980) and Nod2 (605956). Mice lacking both Nod1 and Nod2 were unable to induce early Th17 responses due to insufficient Il6 production. Geddes et al. (2011) concluded that the NOD-innate Th17 axis, which is dependent on IL6 expression and requires intestinal microbiota for induction, is a key element of mucosal immunity against bacterial pathogens.

After injecting mice with anti-CD3 (see 186740) antibody, Esplugues et al. (2011) observed the expected rapid disappearance of most T cells from circulation. However, they also found a concomitant increase in the percentage and number of total T cells in the small intestine, in particular in the duodenum. Immunofluorescence microscopy showed a high frequency of Th17 cells in small intestine. Th17 cell induction was Il6 dependent. Il17 signaling, in turn, led to upregulation of Ccl20 (601960), facilitating migration of Th17 cells to the small intestine. Mouse models of sepsis and influenza A virus infection showed that proinflammatory Th17 cells could be redirected to and controlled in the small intestine. In addition, the proinflammatory cells simultaneously acquired a regulatory phenotype. Esplugues et al. (2011) concluded that Th17 cells, which are beneficial in clearing infection, can be prevented from becoming immunopathogenic by acquiring an immune-suppressive phenotype or by elimination into the intestinal lumen.

Kudva et al. (2011) found that mice lacking Il17a, Il17f, Il17ra, or Il22, all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I and type II IFN in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.

Chen et al. (2012) studied Th2-type immune responses in a mouse model of intestinal nematode parasite infection in which parasite larvae migrate transiently through lung. They found that acute lung injury occurred shortly after worm inoculation and was associated with hemorrhaging, inflammation, decreased lung function, and Ill7 expression. Subsequent Il4r (147781) signaling reduced Il17 expression, enhanced expression of Igf1 (147440) and Il10, and stimulated development of M2-type macrophages, all of which contributed to rapid resolution of tissue damage.

Using chromosome conformation capture, Wang et al. (2012) demonstrated that a cis element, which they termed conserved noncoding sequence-2 (CNS2), located upstream of the Il17 promoter, interacted with the Il17 promoter and also with that for Il17f. Mice lacking Cns2 had impaired Rorc-driven Il17 and Il17f expression in vitro. These cytokine defects were associated with defective chromatin remodeling of the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and Jmjd3 (KDM6B; 611577). CNS2-deficient mice were also resistant to experimental autoimmune encephalomyelitis. Wang et al. (2012) proposed that CNS2 is sufficient and necessary for IL17 and optimal IL17F gene transcription in Th17 cells.

Barin et al. (2013) reported that mice lacking Ifng developed severe experimental autoimmune myocarditis (EAM) following immunization with cardiac myosin peptide (residues 614 to 629 of MYH6, 160710). In contrast, mice lacking Il17a were protected from progression to dilated cardiomyopathy. Double-knockout (DKO) mice lacking both Il17a and Ifng developed rapidly fatal EAM following immunization. Eosinophils constituted one-third of infiltrating leukocytes, allowing the condition to be characterized as eosinophilic myocarditis. Infection of DKO mice with coxsackie virus B3, which is associated with myocarditis in both humans and mouse models, resulted in a similar form of EAM. Flow cytometric analysis of infiltrating Cd4 T cells demonstrated production of Ccl11 (601156), as well as Th2 deviation. DKO mice that also carried a deletion of the high-affinity double GATA-binding site in the Gata1 (305371) promoter, which ablates eosinophil generation, demonstrated improved survival and were at least partially protected from fatal heart failure. Barin et al. (2013) concluded that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.

Tong et al. (2015) found that Il17 -/- mice exhibited attenuated hyperglycemia and insulitis, with fewer Cd8-positive cells infiltrating pancreas, compared with wildtype mice following streptozotocin (STZ)-induced diabetes. Wildtype mice, but not Il17 -/- mice, had increased splenic Cd8-positive cells and decreased Gr1-positive/Cd11b (ITGAM; 120980)-positive myeloid-derived suppressor cells (MDSCs) after STZ treatment. MDSCs from Il17-/- mice showed increased ability to suppress Cd8-positive cell proliferation in vitro and, when transferred to diabetic mice, ameliorated hyperglycemia and reduced splenic Cd8-positive cells. Tong et al. (2015) concluded that Il17 has a pathogenic role in STZ-induced diabetes.

Wynn et al. (2016) found that Il18 -/- neonatal mice were highly protected from polymicrobial sepsis, whereas replenishment of Il18 increased lethality to sepsis or endotoxemia. Increased lethality depended on increased Il1r1 (147810) signaling, but not adaptive immunity. Transcriptomic analysis of human neonates with sepsis revealed elevated levels of IL18, IL18R1 (604494), and IL18RAP (604509), and pathway analysis identified a role for IL17R. In mice, plasma Il17a produced by lamina propria and lung parenchyma cells was significantly amplified following exposure to Il18 and sepsis. Anti-Il17ra blockade or deletion of Il17a ablated the deleterious effects of Il18 on sepsis mortality in mice. Wynn et al. (2016) concluded that IL17A is an effector of IL18-mediated injury in neonatal sepsis and proposed that disruption of the tissue-destructive IL18-IL1-IL17A axis may be a therapeutic approach to improve outcomes in neonatal sepsis.

Using maternal immune activation (MIA) in a mouse model of autism spectrum disorder (ASD; 209850) and genetic mutant mice, Choi et al. (2016) showed that Rorgt-dependent effector T lymphocytes, such as Th17 cells, and Il17a were required in mothers for MIA-induced behavioral abnormalities in offspring. MIA induced a maternal Il17a-dependent abnormal phenotype in cortex of fetal brain. Treating pregnant female mice with antibodies blocking Il17a ameliorated MIA-associated behavioral abnormalities. Choi et al. (2016) proposed that targeting of Th17 cells in susceptible pregnant mothers may reduce the likelihood of them bearing children with inflammation-induced ASD-like phenotypes.

Reed et al. (2020) compared an environmental model of neurodevelopmental disorders in which mice were exposed to MIA during embryogenesis with mouse models that are genetically deficient for Cntnap2 (604569), Fmr1 (309550), or Shank3 (606230). They established that the social behavior deficits in offspring exposed to MIA could be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioral rescue was accompanied by a reduction in neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which had been implicated by Shin Yim et al. (2017) in the manifestation of behavioral phenotypes associated with offspring exposed to MIA. By contrast, Reed et al. (2020) did not observe an LPS-induced rescue of social deficits in the monogenic models. Reed et al. (2020) demonstrated that the differences in responsiveness to the LPS treatment between the MIA and the monogenic models emerged from differences in the levels of cytokine production. LPS treatment in monogenic mutant mice did not induce amounts of Il17a (603149) comparable to those induced in MIA offspring; bypassing this difference by directly delivering Il17a into the S1DZ was sufficient to promote sociability in monogenic mutant mice as well as in MIA offspring. Conversely, abrogating the expression of Il17ra (605461) in the neurons of the S1DZ eliminated the ability of LPS to reverse the sociability phenotypes in MIA offspring. Reed et al. (2020) concluded that their data supported a neuroimmune mechanism that underlies neurodevelopmental disorders in which the production of Il17a during inflammation can ameliorate the expression of social behavior deficits by directly affecting neuronal activity in the central nervous system.


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Contributors:
Ada Hamosh - updated : 06/09/2020
Bao Lige - updated : 10/25/2018
Paul J. Converse - updated : 01/03/2018
Paul J. Converse - updated : 07/28/2016
Paul J. Converse - updated : 06/06/2016
Paul J. Converse - updated : 3/3/2016
Paul J. Converse - updated : 2/4/2016
Ada Hamosh - updated : 10/13/2015
Paul J. Converse - updated : 7/10/2015
Paul J. Converse - updated : 7/8/2015
Paul J. Converse - updated : 4/29/2015
Paul J. Converse - updated : 3/19/2015
Ada Hamosh - updated : 3/12/2015
Paul J. Converse - updated : 1/28/2015
Paul J. Converse - updated : 8/19/2013
Paul J. Converse - updated : 3/12/2013
Ada Hamosh - updated : 12/4/2012
Patricia A. Hartz - updated : 9/21/2012
Paul J. Converse - updated : 6/4/2012
Ada Hamosh - updated : 5/4/2012
Paul J. Converse - updated : 3/8/2012
Paul J. Converse - updated : 2/13/2012
Paul J. Converse - updated : 8/5/2011
Paul J. Converse - updated : 8/5/2011
Paul J. Converse - updated : 4/28/2011
Paul J. Converse - updated : 3/25/2011
Paul J. Converse - updated : 1/24/2011
Paul J. Converse - updated : 7/29/2010
Paul J. Converse - updated : 5/28/2009
Ada Hamosh - updated : 4/2/2009
Paul J. Converse - updated : 11/18/2008
Paul J. Converse - updated : 11/13/2008
Ada Hamosh - updated : 5/21/2008
Paul J. Converse - updated : 3/5/2008
Paul J. Converse - updated : 11/2/2007
Ada Hamosh - updated : 9/11/2007
Paul J. Converse - updated : 7/2/2007
Paul J. Converse - updated : 4/12/2007
Paul J. Converse - updated : 4/4/2007
Paul J. Converse - updated : 8/29/2006
Paul J. Converse - updated : 7/6/2006
Paul J. Converse - updated : 6/23/2006
Paul J. Converse - updated : 5/5/2006
Paul J. Converse - updated : 1/12/2006
Marla J. F. O'Neill - updated : 2/18/2005
Victor A. McKusick - updated : 6/19/2003
Victor A. McKusick - updated : 5/20/1999

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Jennifer P. Macke : 10/15/1998

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