Alternative titles; symbols
HGNC Approved Gene Symbol: IL1B
Cytogenetic location: 2q14.1 Genomic coordinates (GRCh38): 2:112,829,751-112,836,779 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.1 | {Gastric cancer risk after H. pylori infection} | 613659 | 3 |
Interleukin-1, produced mainly by blood monocytes, mediates the panoply of host reactions collectively known as acute phase response. It is identical to endogenous pyrogen. The multiple biologic activities that define IL1 are properties of a 15- to 18-kD protein that is derived from a 30- to 35-kD precursor (summary by March et al., 1985).
Auron et al. (1984) isolated human IL1 cDNA. Cameron et al. (1985) and March et al. (1985) contributed to the delineation of genetically distinct forms of IL1. From the mRNA of lipopolysaccharide (LPS)-stimulated macrophages, March et al. (1985) isolated 2 distinct cDNAs encoding proteins with characteristic IL1 activity, defined by the induction of IL2 synthesis by a T-cell line or by thymocytes. They termed the proteins IL1-alpha (147760) and IL1-beta. These show only distant homology to each other (26% at the protein level, 45% at the nucleic acid level). Each appears to be synthesized as a large precursor (with deduced molecular masses of 30.6 and 30.7 kD, respectively) that is processed to a smaller form.
Gray et al. (1986) cloned mouse Il1b, which encodes a 269-residue protein that is 67% homologous to human IL1B. Il1b mRNA was about 5-fold more abundant than Il1a in a stimulated macrophage cell line.
With the cDNA probe of Auron et al. (1984), Webb et al. (1985, 1986) assigned the IL1 gene to chromosome 2. By in situ hybridization they localized it to q13-q21. Presumably this is the beta form of IL1 because the deduced molecular weight was 30,747. Le Beau and Rowley (1986), using a probe presumably of the alpha form, found in situ hybridization to the same region, 2q13-q21, where the presumed IL1B probe was assigned by Webb et al. (1985, 1986); contrariwise, Le Beau and Rowley (1986) assigned IL1B to the end of 18q. By Southern blot analysis of DNA from a hamster/mouse somatic cell hybrid, D'Eustachio et al. (1987) demonstrated that the 2 polypeptides of IL1, alpha and beta, are coded by mouse chromosome 2. Furthermore, the analysis of the inheritance of RFLPs associated with each gene in recombinant inbred strains of mice showed that the 2 loci, symbolized Il-1a and Il-1b, are tightly linked and lie approximately 4.7 cM distal to beta-2-microglobulin. The linkage with B2m, which is on human chromosome 15, is clearly not conserved in man. On the other hand, at least 1 gene on human chromosome 2, glucagon (138030), is coded by chromosome 2 in the mouse.
Using a YAC containing the interleukin-1 receptor antagonist gene (IL1RN; 147679) as a probe in fluorescence in situ hybridization, Patterson et al. (1993) assigned the IL1RN gene to 2q14.2. From restriction mapping of the human genomic region containing the 3 related genes, Nicklin et al. (1994) concluded that, relative to one terminal CpG island, the 3 genes mapped to the following intervals: IL1A was between +0 and +35 kb, IL1B between +70 and +110 kb, and IL1RN between +330 and +430 kb. Since the assignment of IL1RN to 2q14.2 appears to be the most definitive localization, the IL1A and IL1B genes can be presumably be said to be also on 2q14.
Nicklin et al. (2002) determined that the gene order within the IL1 gene cluster on chromosome 2, from centromere to telomere, is IL1A-IL1B-IL1F7 (IL37; 605510)-IL1F9 (IL36G; 605542)-IL1F6 (IL36A; 605509)-IL1F8 (IL36B; 605508)-IL1F5 (IL36RN; 605507)-IL1F10 (615296)-IL1RN. Of these, only IL1A, IL1B, and IL36B are transcribed toward the centromere.
The adhesion of circulating cancer cells to capillary endothelia is a critical step in the initiation of metastasis. Vidal-Vanaclocha et al. (2000) reported results demonstrating a role for IL1B and IL18 (600953) in the development of hepatic metastases of melanoma in vivo. In vitro, soluble products from mouse melanoma cells stimulated hepatic sinusoidal endothelium to sequentially release tumor necrosis factor-alpha (TNFA; 191160), IL1B, and IL18. The IL18 cytokine increased expression of vascular cell adhesion molecule-1 (VCAM1; 192225) and the adherence of melanoma cells.
Inflammation causes the induction of COX2 (600262), leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighboring uninjured tissue, because of the increased neuronal excitability in the spinal cord, and a syndrome comprising diffuse muscle and joint pain, fever, lethargy, and anorexia. Samad et al. (2001) showed that COX2 may be involved in central nervous system (CNS) responses, by finding a widespread induction of COX2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central COX2 upregulation is IL1B in the CNS, and as basal phospholipase A2 (see 600522) activity in the CNS does not change with peripheral inflammation, COX2 levels must regulate central prostanoid production. In the rat, intraspinal administration of an interleukin-converting enzyme or COX2 inhibitor decreased inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, Samad et al. (2001) concluded that preventing central prostanoid production by inhibiting the IL1B-mediated induction of COX2 in neurons or by inhibiting central COX2 activity reduces centrally generated inflammatory pain hypersensitivity.
Baek et al. (2002) demonstrated that IL1B causes nuclear export of a specific NCOR (600849) corepressor complex, resulting in derepression of a specific subset of nuclear factor-kappa-B (NFKB; see 164011)-regulated genes. These genes are exemplified by the tetraspanin KAI1 (600623), which regulates membrane receptor function. Nuclear export of the NCOR/TAB2 (605101)/HDAC3 (605166) complex by IL1B is temporally linked to selective recruitment of a TIP60 (601409) coactivator complex. KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of the beta amyloid precursor protein (APP; 104760), FE65 (602709), and TIP60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Voronov et al. (2003) showed that microenvironmental IL1-beta and, to a lesser extent, IL1-alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. Furthermore, they reported antiangiogenic effects of IL1RN, suggesting a possible therapeutic role in cancer, in addition to its use in rheumatoid arthritis.
Progressive oligodendrocyte loss is part of the pathogenesis of multiple sclerosis (MS; 126200). Oligodendrocytes are vulnerable to a variety of mediators of cell death, including free radicals, proteases, inflammatory cytokines, and glutamate excitotoxicity. Proinflammatory cytokine release in MS is mediated in part by microglial activation. Takahashi et al. (2003) found that IL1B, a prominent microglia-derived cytokine, caused oligodendrocyte death in coculture with astrocytes and microglia, but not in pure culture of oligodendrocytes alone. Because IL1B had been shown to impair the activity of astrocytes in the uptake and metabolism of glutamate, Takahashi et al. (2003) hypothesized that the indirect toxic effect of microglia-derived IL1B on oligodendrocytes involved increased glutamate excitotoxicity via modulation of astrocyte activity. In support, antagonists at glutamate receptors blocked the toxicity of IL1B. Similar studies of TNF-alpha, another microglia-derived cytokine, yielded the same results. The findings provided a mechanistic link between microglial activation in MS with glutamate-induced oligodendrocyte destruction.
In 17 of 17 patients who had died of sudden infant death syndrome (SIDS; 272120), Kadhim et al. (2003) detected high IL1B immunoreactivity in the arcuate and dorsal vagal nuclei in the brainstem compared to controls.
In studies of the effect of statin drugs on IL1A, IL1B, and IL1RN levels in individuals with and without coronary artery disease (CAD), Waehre et al. (2004) found that IL1A and IL1B mRNA levels were markedly reduced in peripheral blood mononuclear cells (PBMCs) from CAD patients after 6 months of statin therapy, with a lesser reduction in IL1RN. IL1A, IL1B, and IL1RN mRNA levels were increased in patients with stable and unstable angina compared to controls; particularly high levels of IL1A and IL1B were seen in the unstable patients, who did not, however, have correspondingly high IL1RN levels, suggesting a net inflammatory dominance in those patients. IL1B induced the release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished that effect.
During the development of atherosclerotic plaques, vascular smooth muscle cells change from the physiologic contractile phenotype to the pathophysiologic synthetic phenotype. They then migrate into the intima where they proliferate and produce extracellular matrix. Chen et al. (2006) found that PDGFB (190040) and IL1B cooperate in inducing contractile-to-synthetic phenotype modulation of human aortic smooth muscle cells in culture. Phenotypic modulation by PDGFB and IL1B involved crosstalk between their corresponding receptors PDGFRB (173410) and IL1R1 (147810) and was mediated through the PI3K (see 171834)/AKT (see 164730)/P70S6K (608938) signaling pathway.
Greten et al. (2007) found that mice deficient in the NF-kappa-B regulator Ikkb (IKBKB; 603258) in myeloid cells showed increased levels of Il1b following endotoxin challenge or bacterial infection due to enhanced pro-Il1b processing. Prolonged pharmacologic inhibition of Ikkb, which interferes with NF-kappa-B activation in the whole animal, also increased LPS-induced mortality and plasma Il1b. Greten et al. (2007) concluded that IKKB-dependent NF-kappa-B activation has a role in reducing IL1B secretion.
Gross et al. (2009) demonstrated that the tyrosine kinase Syk (600085), operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL1-beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signaling for pro-IL1-beta synthesis selectively uses the Card9 (607212) pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmacologic inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (606416) was identified as the critical NOD (see 605980)-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (PYCARD; 606838) for caspase-1 (CASP1; 147678) activation and pro-IL1-beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, Gross et al. (2009) showed that Nlrp3-deficient mice are hypersusceptible to C. albicans infection. Thus, Gross et al. (2009) concluded that their results demonstrated the molecular basis for IL1-beta production after fungal infection and identified a crucial function for the Nlrp3 inflammasome in mammalian host defense in vivo.
Ben-Sasson et al. (2009) reported that Il1-alpha and Il1-beta, but not other proinflammatory cytokines, markedly induced robust and durable primary and secondary Cd4 (186940) responses in mice, with an increase in cells producing Il17 (see 603149) and Il4 (147780), as well as serum IgG1 and IgE.
CD4+ T helper cells that selectively produce IL17 (Th17) are critical for host defense and immunity. Ghoreschi et al. (2010) showed that Th17 differentiation can occur in the absence of TGF-beta (190180) signaling. Neither IL6 (147620) nor IL23 (605580) alone efficiently generated Th17 cells; however, these cytokines in combination with IL1-beta effectively induced IL17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the IL17A, IL17F (606496), and RORC (602943) promoters proceeded without TGF-beta-1, allowing the generation of cells that coexpressed ROR-gamma-t (encoded by RORC) and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred Th17 cells generated with IL23 without TGF-beta-1 were pathogenic in this disease model. Ghoreschi et al. (2010) concluded that their data indicated an alternative mode for Th17 differentiation, and that, consistent with genetic data linking IL23R (607562) with autoimmunity, their findings reemphasized the importance of IL23 and therefore may have therapeutic implications.
Francisella tularensis, the causative agent of tularemia and a potential biohazard threat, evades the immune response, including innate responses through the lipopolysaccharide receptor TLR4 (603030), thus increasing its virulence. Huang et al. (2010) deleted the bacterium's ripA gene and found that mouse macrophages and a human monocyte line produced significant amounts of the inflammatory cytokines TNF, IL18, and IL1B in response to the mutant. IL1B and IL18 secretion was dependent on PYCARD and CASP1, and MYD88 (602170) was required for inflammatory cytokine synthesis. A complemented strain with restored expression of ripA restored immune evasion, as well as activation of the MAP kinases ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), JNK (see 601158), and p38 (MAPK14; 600289). Pharmacologic inhibition of these MAPKs reduced cytokine induction by the ripA deletion mutant. Mice infected with the mutant exhibited stronger Il1b and Tnfa responses than mice infected with the wildtype live vaccine strain. Huang et al. (2010) concluded that the F. tularensis ripA gene product functions by suppressing MAPK pathways and circumventing the inflammasome response.
Pathak et al. (2011) studied plasma and peripheral blood cell expression of IL1B, MMP9 (120361), soluble IL1R2 (147811), and IL17 in 47 patients with either autoimmune inner ear disease or sensorineural hearing loss of likely immunologic origin who were treated with corticosteroids. They found that 18 corticosteroid nonresponder patients expressed significantly higher levels of IL1B and MMP9, but not IL17 or soluble IL1R2, compared with clinically responsive patients. RT-PCR analysis showed that treating control blood cells with IL1B induced expression of MMP9. Treatment with the MMP9 catalytic domain plus dexamethasone, but not MMP9 alone, reciprocally induced IL1B expression. Treatment of cells with dexamethasone alone increased IL1R2 expression in cells and plasma, and IL1R2 expression was further increased with the addition of MMP9. In responder patient cells, treatment with dexamethasone reduced expression of IL1B and MMP9, whereas IL1B expression could only be reduced in nonresponder cells by treatment with anakinra, the soluble IL1R antagonist (IL1RN; 147679). Pathak et al. (2011) proposed that IL1B blockade may be a viable therapy for patients with autoimmune inner ear disease or sensorineural hearing loss that fail to respond to corticosteroids.
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 (603149) and IFN-gamma (IFNG; 147570) 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 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 (see 602943). 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.
Zhu et al. (2012) showed that the direct, immediate, and disruptive effects of IL1-beta on endothelial stability in a human in vitro cell model are NF-kappa-B (see 164011)-independent and are instead the result of signaling through the small GTPase ADP-ribosylation factor-6 (ARF6; 600464) and its activator ARF nucleotide-binding site opener (ARNO; 602488). Moreover, Zhu et al. (2012) showed that ARNO binds directly to the adaptor protein MYD88 (602170), and thus proposed MYD88-ARNO-ARF6 as a proximal IL1-beta signaling pathway distinct from that mediated by NF-kappa-B. Finally, Zhu et al. (2012) showed that SecinH3, an inhibitor of ARF guanine nucleotide exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.
Tannahill et al. (2013) showed that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced IL1B but not tumor necrosis factor-alpha (TNFA; 191160) in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages showed upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increased the levels of the tricarboxylic acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'gamma-aminobutyric acid (GABA) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor 1-alpha (HIF1A; 603348), an effect that is inhibited by 2-deoxyglucose, with IL1B as an important target. Lipopolysaccharide also increased succinylation of several proteins. Tannahill et al. (2013) concluded that they identified succinate as a metabolite in innate immune signaling that enhances IL1B production during inflammation.
Mishra et al. (2013) infected mice lacking nitric oxide (NO) synthase-2 (NOS2A; 163730) with a strain of M. tuberculosis (see 607948) whose growth could be controlled exogenously. Using these mice, they found that Ifng and NO suppressed both bacterial growth in vivo and the continual production of Il1b by the Nlrp3 inflammasome, thereby inhibiting persistent neutrophil recruitment and preventing tissue damage. Mishra et al. (2013) concluded that NO has a dual role in promoting resistance to M. tuberculosis and in regulating inflammation, both of which are required for survival of this chronic infection.
Arbore et al. (2016) found that the NLRP3 inflammasome assembled in human CD4-positive T cells and initiated CASP1-dependent IL1B secretion, thereby promoting IFNG production and T-helper-1 (Th1) differentiation in an autocrine fashion. NLRP3 assembly required intracellular C5 (120900) activation and stimulation of C5AR1 (113995), and this process was negatively regulated by C5AR2 (609949). Aberrant NLRP3 activity in T cells affected inflammatory responses in patients with cryopyrin-associated periodic syndrome (FCAS1; 120100) and in mouse models of inflammation and infection. Arbore et al. (2016) concluded that NLRP3 inflammasome activity is involved in normal adaptive Th1 responses, as well as in innate immunity.
Naik et al. (2017) reported a prolonged memory to acute inflammation that enables mouse epithelial stem cells (EpSCs) to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fueling this memory is Aim2 (604578), which encodes an activator of the inflammasome. The absence of Aim2 or its downstream effectors, caspase-1 (147678) and interleukin-1-beta, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
Association with Helicobacter pylori and Cancer
El-Omar et al. (2000) reported that interleukin-1 gene cluster polymorphisms suspected of enhancing production of interleukin-1-beta are associated with an increased risk of both hypochlorhydria induced by Helicobacter pylori and gastric cancer (see 613659). One of these is a TATA-box polymorphism that markedly affects DNA-protein interactions in vitro. The association with disease may be explained by the biologic properties of interleukin-1-beta, which is an important proinflammatory cytokine and a powerful inhibitor of gastric acid secretion. Host genetic factors that affect interleukin-1-beta may determine why some individuals infected with H. pylori develop gastric cancer while others do not. IL1-beta is upregulated in the presence of H. pylori and is important in initiating and amplifying the inflammatory response to this infection. Three diallelic polymorphisms in IL1B have been reported, all representing C-to-T base transitions, at positions -511, -31, and +3954 basepairs from the transcriptional start site. To determine whether these polymorphisms are important with respect to different outcomes of H. pylori infections, El-Omar et al. (2000) studied their effects on gastric physiology in healthy subjects. Carriers of the ILB -31T allele (147720.0001) had an age-adjusted odds ratio of 9.1 (95% confidence interval, 2.2-37) for low acid secretion, and there was little difference between homozygous and heterozygous carriers. The IL1B +3954 genotype was not associated with the risk of hypochlorhydria. Carriers of IL1B -31T had an increased gastric cancer risk at an odds ratio of 1.9 (95% confidence interval, 1.5-2.6), with no significant difference between homozygotes and heterozygotes. El-Omar et al. (2000) demonstrated that the proinflammatory genotypes of the IL1 loci (IL1B -31T and IL1RN/IL1RN*2; 147679.0001) increase both the likelihood of a chronic hypochlorhydric response to H. pylori infection and the risk of gastric cancer, presumably by altering IL1-beta levels in the stomach. This increased production of IL1-beta favors the initiation of a set of responses to H. pylori that result in hypochlorhydria, corpus atrophy, and increased risk of gastric cancer.
Other Possible Associations
Mwantembe et al. (2001) noted that inflammatory bowel disease (see IBD1, 266600) is more prevalent in South African whites than in blacks, a pattern observed elsewhere as well. By restriction enzyme and linkage disequilibrium analysis of IL1B, IL1RA (147810), and IL1RN polymorphisms, Mwantembe et al. (2001) determined that a mutant IL1B allele (Taq-) was significantly more common in white patients than in white controls, whose frequency was similar to black patients and controls. On the other hand, a mutant IL1RA allele (Pst-) was significantly more frequent in blacks than in whites, regardless of disease status. Although other population differences were observed, no other alleles were significantly associated with disease in either group. Plasma IL1RN levels were significantly higher in black patients than in black controls or white patients and controls. Plasma concentrations of the alpha-1 protease inhibitor (PI; 107400), an indicator of inflammation, were significantly higher in both black and white patients than in black and white controls. Mwantembe et al. (2001) concluded that the inflammatory processes leading to IBD may be distinct in the different population groups.
Interleukin-1-beta is a potent stimulator of bone resorption, and has been implicated in the pathogenesis of high bone turnover and osteoporosis. IL1RN is a competitive inhibitor of IL1B effects, and the biologic effects of IL1B are therefore proportional to the ratio of IL1B to IL1RN. Langdahl et al. (2000) examined the coding regions of IL1B for sequence variations. They found no sequence variations in IL1B other than previously described polymorphisms. The distribution of the polymorphic genotypes was similar in osteoporotic patients and normal controls. They found no significant differences in bone mass or bone turnover. On the other hand, specific genotypes of the IL1RN VNTR polymorphism were found to be increased in osteoporotic patients compared with age-matched normal controls. Langdahl et al. (2000) concluded that an 86-bp repeat polymorphism in IL1RN is associated with increased risk of osteoporotic fractures. Other polymorphisms in the IL1RN and IL1B genes are not associated with osteoporotic fractures or alterations in bone mass or bone turnover.
Among 395 patients with Alzheimer disease (AD; 104300), Green et al. (2002) found no association between the IL1A -889 and IL1B -511 polymorphisms and increased risk of AD.
Among 52 Finnish patients with Parkinson disease (PD; 168600), Mattila et al. (2002) found an increased frequency of the IL1B -511 polymorphism compared to controls (allele frequency of 0.96 in PD and 0.73 in controls; p = 0.001). The calculated relative risk of PD for patients carrying at least one IL1B allele was 8.8. Among 92 Finnish patients with late-onset AD, no association was found with the IL1B -511 or IL1A -889 polymorphisms.
Strandberg et al. (2006) hypothesized that common polymorphisms of the IL1 system, which are associated with IL1 activity, also are associated with fat mass. Three different polymorphisms, IL1-beta +3953 C/T, IL1-beta -31 T/C (147720.0001), and IL1 receptor antagonist (IL1RN; 147679) VNTR of 86 bp, were investigated in relation to body fat mass. Carriers of the T variant (CT and TT) of the +3953 C to T (FT = 0.25) IL1-beta gene polymorphism had significantly lower total fat mass (p = 0.013) and also significantly reduced arm, leg, and trunk fat, compared with CC individuals. IL1RN*2 (147679.0001) carriers with 2 repeats of the IL1RN VNTR polymorphism had increased total fat (p = 0.036), serum leptin, and fat of trunk and arm as well as serum levels of IL1RN and IL1RN production ex vivo. The IL1-beta -31 polymorphism did not correlate with the fat measurements. The authors concluded that the IL1 system, shown to affect fat mass in experimental animals, contains gene polymorphisms that are associated with fat mass in young men.
For discussion of an association between diabetic nephropathy and the -511C-T polymorphism in the IL1B gene, see MVCD4 (612628).
For discussion of a possible association between the -31C-T SNP in the IL1B gene and susceptibility to tuberculosis (TB; see 607948), see 147720.0001.
Mature IL1-beta levels are a sensitive and specific indicator of caspase-1 (147678) activation. Ona et al. (1999) studied the effect of inhibition of caspase-1 on the progression of Huntington disease (143100) in the mouse model developed by Mangiarini et al. (1996), which they called R6/2 mice. Ona et al. (1999) crossed R6/2 mice with a well-characterized transgenic mouse strain expressing a dominant-negative mutant of caspase-1 in the brain (NSE M17Z). Double mutant mice showed extended survival and delayed appearance of neuronal inclusions, neurotransmitter receptor alterations, and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of Huntington disease. Mature IL1-beta levels in R6/2 mice were elevated to 268% of those in wildtype controls. This increase was significantly inhibited in the R6/2-NSE M17Z mice. IL1-beta levels in the brains of human patients also exhibited significant increases, to 213% of those in normal controls.
To investigate the severe arthritis induced in BALB/c mice by K/BxN serum, Ohmura et al. (2005) used selective breeding to map intervals and genes associated with high susceptibility for aggressive arthritis and identified Il1b as a key determinant of susceptibility. Susceptible mice showed a 10-fold greater induction of Il1b mRNA compared with a resistant strain of mice following lipopolysaccharide injection. Arthritis susceptibility was associated with a particular set of polymorphisms in promoter and intron sequences of the Il1b gene that affected transcription or splicing efficiency, but not mRNA stability. No susceptibility polymorphisms were identified in the Il1b coding region. Ohmura et al. (2005) concluded that genetic polymorphism at IL1B is a determinant of arthritis severity.
Del Rey et al. (2006) demonstrated that endogenous levels of Il1b induced hypoglycemia and triggered Il1b gene expression in the hypothalamus of normal and insulin-resistant mice; Il1b-induced hypoglycemia was largely antagonized by blockade of Il1r1 (147810) in the brain. IL1B had a prolonged hypoglycemic effect that was insulin-independent and developed against increased levels of glucocorticoids, catecholamines, and glucagon. Del Rey et al. (2006) concluded that IL1B can reset glucose homeostasis at central levels.
Soller et al. (2007) reported that canine Tnf, Il1a, and Il1b have high coding and protein sequence identity to human and other mammalian homologs. They suggested that dog models of cytokine-mediated human diseases may be highly informative.
Using mice lacking both Il1a and Il1b, Oboki et al. (2010) showed that Il1 played a substantial role in the induction of T cell-mediated type IV hypersensitivity, including contact and delayed-type hypersensitivity reactions, and autoimmune diseases, such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis (MS; 126200).
Using a mouse model of mucosal Candida albicans infection, Hise et al. (2009) showed that Tlr2 (603028) and dectin-1 (CLEC7A; 606264) controlled Il1b transcription, whereas Nlrp3, Asc, and Casp1 regulated processing of pro-Il1b into the active, mature 17-kD protein. Tlr2, dectin-1, and the Nlrp3 inflammasome were essential for defense against disseminated infection and mortality in vivo. Mice lacking Il1r had increased fungal burden in tongue. Hise et al. (2009) concluded that the NLRP3 inflammasome and IL1B production have essential roles in the regulation of mucosal antifungal host defense.
A C-T SNP at position -31 from the transcription start site (rs1143627) involves the TATA sequence in the IL1B promoter. Using electrophoretic mobility shift analysis to assess DNA binding in vitro, El-Omar et al. (2000) found that the IL1B -31T allele was associated with a 5-fold increase in DNA binding after lipopolysaccharide stimulation. Individuals carrying the IL1B -31T allele were at higher risk of hypochlorhydria and of gastric cancer after H. pylori infection (see 613659).
Hamajima et al. (2001) observed the near complete linkage of the -31C/-511T and -31T/-511C IL1B alleles in 241 Japanese non-cancer outpatients participating in an H. pylori eradication program. They determined that the C-to-T transition at position -31, creating a TATA box, is associated with vulnerability to persistent H. pylori infection, and that the susceptibility is modified by smoking. They noted that this linkage was opposite to that reported in Caucasian subjects (El-Omar et al., 2000). Prompted by the report of Hamajima et al. (2001), El-Omar et al. (2000) reviewed and corrected their own data. In an erratum, El-Omar et al. (2000) stated that consistent with the observation of Hamajima et al. (2001), -511T/-31C is the correct linkage in Caucasians.
Among 310 individuals from eastern India, Chakravorty et al. (2006) found that the frequency of the IL1B -31TT genotype was 0.071 compared to 0.37 as reported in Caucasians. Among the Indian population, they observed a significantly higher frequency of the IL1B -511TT genotype (OR of 4.22) and -31CC genotype (OR of 2.16) in H. pylori-infected persons with duodenal ulcer compared to infected persons with normal mucosa. The -511T/-31C haplotype was present at a higher frequency in H. pylori-infected duodenal ulcer patients than in infected controls (OR of 2.47). Carriers of the -31CC genotype had significantly lower IL1B mRNA levels in gastric mucosa compared to other genotypes, and IL1B promoter assay showed that the -31T promoter had a 10-fold increase in activity compared to -31C. Chakravorty et al. (2006) suggested that H. pylori-infected individuals with the -31CC genotype secrete less IL1B and are susceptible to duodenal ulcers.
Possible Association with Tuberculosis Susceptibility
Zhang et al. (2014) examined the genotype distribution of 4 IL1B SNPs with potential regulatory effects in 2 independent Chinese populations with tuberculosis (TB; see 607948) and 2 independent sets of healthy controls (1,799 total TB cases and 1,707 total controls). They found that only the frequency of the T allele of the -31C-T SNP in the IL1B promoter was significantly higher in patients with active TB, both pulmonary and extrapulmonary. High-resolution computer-assisted tomography analysis indicated that the -31T allele was associated with more severe pulmonary TB than the -31C allele. Stimulation of monocytes with Mycobacterium tuberculosis (Mtb) antigens resulted in higher amounts of IL1B protein and mRNA, but not of IL1R antagonist (IL1RN; 147679), in healthy controls carrying -31TT or -31TC compared with those carrying -31CC. Stimulation of PBMCs with Mtb antigens resulted in no significant differences in IFNG (147570) or IL17 (603149) production in controls; however, stimulation was associated with higher IFNG production in TB patients carrying -31TT. Analysis of bronchoalveolar lavage fluid from patients with active TB showed that higher IL1B production was associated with higher neutrophil recruitment. EMSA supershift analysis detected higher binding of CEBPA (116897) and PU.1 (SPI1; 165170) to the -31T oligonucleotide compared with the -31C oligonucleotide. Zhang et al. (2014) concluded that the higher IL1B production and neutrophil recruitment associated with -31T lead to increased tuberculosis susceptibility, tissue-damaging inflammatory responses, and accelerated disease progression.
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