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Cytokines, Chemokines and Their Receptors

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The immune system is skilled in communication and designed to respond quickly, specifically and globally to protect an organism against foreign invaders and disease. The cytokine superfamily of proteins is an integral part of the signaling network between cells and is essential in generating and regulating the immune system. Much progress has been made recently in interpreting how the immune system communicates with, or is mediated by, cytokines and chemotactic cytokines (chemokines). These interacting biological signals have remarkable capabilities, such as influencing growth and development, hematopoiesis, lymphocyte recruitment, T cell subset differentiation and inflammation. This chapter provides brief synopses for a comprehensive list of immune-related cytokines and chemokines. Information such as gene cloning and mapping details, protein characteristics and expression, receptor usage, source and target cells, major biological functions and knockout phenotype is described for each cytokine and chemokine. With an approach that organizes cytokines and chemokines into interacting groups with related physical and/or functional properties, this chapter aims to highlight the capability of this system to maintain widespread impact and functional complementation while not sacrificing regulation and specificity of action. A more complete understanding of these properties may lead to more advanced means of correcting improper cytokine- or chemokine-mediated immune responses, such as those causing autoimmune disease.

Detailed and reliable communication must occur through a complex system of network connections to accomplish a task at a modern workstation. In parallel, the immune system is an interdependent biological network charged with developmental tasks and the responsibility of protecting its host against injury and infection. An immune cell within a given microenvironment can respond to signals received through its receptors with its own protein-based language that will influence the cell itself (autocrine effect) or other cells throughout the organism (paracrine effect). The language of cytokines is critical in this communication. Cytokines are small soluble factors with pleiotropic functions that are produced by many cell types as part of a gene expression pattern that can influence and regulate the function of the immune system.

The term cytokine was proposed by Cohen et al in 19741 to replace lymphokine, a term coined in the late 1960's to denote lymphocyte-derived soluble proteins that possess immunological effects.2 Since the latter designation misleadingly suggested that lymphocytes were the only source for these secreted proteins, the term cytokine slowly became preferred. Following the introduction of this general term, the Second International Lymphokine Workshop held in 1979 proposed the interleukin (IL) system of nomenclature to simplify the growing list of identified cytokines. Ironically, this partially adopted system introduced confusion in that the interleukins, presently numbering at least 23, affect many cell types but their name implies that they act only among leukocytes. As a result, modern cytokine nomenclature is a mix of the widely accepted, but slightly misleading, interleukin designations and other proteins still known by their original names. A good example of these potential points of confusion is the chemotactic cytokine (chemokine) IL-8, which is produced by and targets a wide variety of cell types including leukocytes and nonleukocytes.

As this chapter unfolds, repeated mention of a number of cytokines and chemokines will make it clear that these proteins can be part of a bigger immune program, e.g., T cell subset differentiation. Mature CD4 and CD8 T cells leave the thymus with a naive phenotype and produce a variety of cytokines. In the periphery, these T cells encounter antigen presenting cells (APCs) displaying either major histocompatibility complex (MHC) class I molecules (present peptides generated in the cytosol to CD8 T cells) or MHC class II molecules (present peptides degraded in intracellular vesicles to CD4 T cells). Following activation, characteristic cytokine and chemokine secretion profiles allow the classification of CD4 T helper (Th) cells into two major subpopulations in mice and humans.3-7Th1 cells secrete mainly IL-2, interferon-γ (IFN-γ) and tumor necrosis factor-β (TNF-β), whereas Th2 cells secrete mainly IL-4, IL-5, IL-6, IL-10 and IL-13. Th1 cells support cell-mediated immunity and as a consequence promote inflammation, cytotoxicity and delayed-type hypersensitivity (DTH). Th2 cells support humoral immunity and serve to downregulate the inflammatory actions of Th1 cells. This paradigm is a great example of an integrated biological network and is very useful in simplifying our understanding of typical immune responses and those that turn pathogenic. For example, the failure to communicate “self” can lead to a loss of tolerance to our own antigens and prompt destructive immune responses to self-tissues and autoimmune disease. Autoimmunity, the major focus of this book, is the underlying mechanism of a set of conditions, such as type 1 diabetes mellitus, multiple sclerosis and rheumatoid arthritis. Autoimmune diseases may be caused in part by cytokine- and chemokine-mediated dysregulation of Th cell subset differentiation. The main factors affecting the development of Th subsets, aside from the context in which the antigen and costimulatory signals are presented, are the cytokines and chemokines in the stimulatory milieu. A better understanding of the properties and interactions of the individual cytokines and chemokines that play a role in Th cell activation may lead to more advanced treatments for autoimmune disease.

The proceeding sections will introduce many of the currently identified cytokines and chemokines, along with their receptors. You will find that cytokines and chemokines with related structure and/or function are clustered into groups of interdependent homologues, e.g., the IL-1-like cytokines. A particular group of cytokines or chemokines can exhibit functional redundancy with, and widespread impact on, other groups of cytokines or chemokines, e.g., IL-1-like cytokines and IL-6-like cytokines. Interestingly, this can occur while maintaining several regulatory features, such as internal checkpoints and specificity of action. It is therefore hoped that this chapter may serve as more than a brief catalogue of the field of cytokines, chemokines and their receptors, but may also highlight the remarkable capabilities of this interacting network of biological signals.

Cytokines, their Receptors and their Genes

Table 1 introduces the human cytokines and lists some of their properties, such as receptor usage and physical characteristics. Each human cytokine described in Table 1 has a murine counterpart so the basic list can be used interchangeably in regards to terminology. Hundreds of cytokines have been identified. In the interest of conciseness the table includes only common cytokines with recognized immune function, many of which are discussed in more detail below. Excluded are the ‘growth factors’, neurobiological proteins and ‘trophins’, for example. It is also beyond the scope of this chapter to describe how cytokines signal through their receptors in any detail. One popular cytokine signaling mechanism used by cytokines such as IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15 and the interferons, however, begins with dimerization of the appropriate receptor chains upon ligand binding. Following this, different types of receptor-associated Janus family tyrosine kinases (Jak) are activated which phosphorylate the receptor chains and allow the recruitment and activation of other kinases and transcription factors, such as those of the signal transducer and activator of transcription (Stat) family. This promotes the rapid translocation of these proteins to the nucleus and stimulation of target gene transcription (see references 8 and 9 for more details on cytokine signaling).

Table 1. Common human cytokines and their receptors1.

Table 1

Common human cytokines and their receptors1.

IL-1-Like Cytokines

Firstly, the interleukins are comprised mostly of hematopoietic growth factors and can be further divided into groups of proteins as shown in Table 1. The IL-1-related group of pro-inflammatory cytokines consists of IL-1α, IL-1β, IL-1 receptor antagonist (IL-1RA) and IL-18. IL-1α and IL-1βare produced mainly by mononuclear and epithelial cells upon inflammation, injury and infection.10 These two proteins are of primary importance to the outcome of these challenges to the immune system in that they trigger fever, induce a wide variety of acute phase response (APR) genes and activate lymphocytes.10 IL-1α and IL-1β arise from two closely linked genes that, along with the IL-1RA gene, lie on human (and mouse) chromosome 2.10,11The two forms of IL-1 are quite similar in function since they both signal through the IL-1 type 1 receptor (IL-1-R1/CD121a).12 Both proteins can also bind to the IL-1 type 2 receptor (IL-1-R2/CDw121b) which does not appear to be involved in signaling, except as a possible decoy.13 The IL-1 receptor genes are located on human chromosome 2 along with their ligands, albeit at a distance.

Murine knockout studies confirm the importance of IL-1 in fever responses and the APR. While at least three studies involving the IL-1β knockout mouse demonstrate that fever development is suppressed upon turpentine or lipopolysaccharide (LPS) challenge,14-16one study demonstrates that the role of IL-1β as a pyrogen is not obligatory and that its absence can in fact exacerbate an induced fever response.17 The latter conflicting result may stem from differences in experimental protocol or reagents.14 Knockout studies also show that while both forms of IL-1 can induce fever responses, fever induction is not reduced in IL-1α knockout mice, indicating that IL-1βcan compensate for IL-1α but not vice versa.14 The role for IL-1 in the APR (a series of cellular and cytokine cascades in reaction to trauma or infection that help limit damage) was confirmed in a localized tissue damage model of turpentine injection where challenged IL-1β-deficient mice did not develop an APR.18 Accordingly, IL-1R1 knockout mice are irresponsive to IL-1 in the induction of IL-6, E-selectin and fever.18 These mice also have a reduced APR to turpentine.19

IL-1RA is produced by virtually any cell that can produce IL-1 and is similar in structure to IL-1β but lacks its agonist activity.20 The different species of IL-1RA, a secreted form with a signal peptide and at least two intracellular forms, arise from alternative splicing of different first exons on chromosome 2.20,21 IL-1RA represents an intriguing example of a naturally occurring cytokine receptor antagonist. IL-1RA may be an acute phase protein that may serve to regulate the agonist effects of IL-1 during chronic inflammatory and infectious disease because its expression is influenced by cytokines, viral and bacterial products, bound antibody and acute phase proteins, such as IL-1, IL-4, IFN-γ and LPS.20 Consistent with this notion are two studies of IL-1RA-deficient mice which exhibit growth retardation, an exacerbated fever response to turpentine injection, increased lethality following LPS injection and decreased susceptibility to Listeria monocytogenes.14,22These observations verify the importance of balance in the IL-1 system in mediating these immune challenges.

IL-18, initially termed interferon-γ inducing factor (IGIF), is a pro-inflammatory cytokine that is encoded on human chromosome 11 and mouse chromosome 9.23 IL-18 has been placed in the IL-1 group of interleukins because it bears structural homology to IL-1α and β, is converted into a mature form by IL-1β converting enzyme (ICE) along with IL-1β and binds to the IL-18 receptor (IL-18R or IL-1R related protein).23 The IL-18R resembles the IL-1R and transduces IL-1R signaling.23 IL-18 shares biological function with IL-12 in that it induces IFN-γ secretion (in synergy with IL-12), enhances natural killer (NK) cell activity and promotes inflammatory Th1 cell responses.23 Accordingly, when IL-1824 or its receptor25 is knocked out, mice exhibit defective NK cell activity and Th1 responses. More recently, however, the role of IL-18 as a pro-inflammatory cytokine has been questioned because IL-18 can also potentiate regulatory Th2 responses, perhaps by inducing IL-4 production by natural killer T (NKT) cells in certain situations.26-28

Common γChain Cytokines

Cytokines that utilize the common γ chain (γc/CD132) in their receptor comprise the next group of interleukins, namely IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15. These diverse cytokines invoke lymphocyte activation and differentiation (the outcome of which can vary) and possess some redundancy in biological function because of their common receptor subunit.29 The γc itself cannot bind cytokines; however, new evidence suggests that it can be shed as a soluble negative modulator.30 Indeed, γc-deficient mice are severely immunocompromised, as are humans with γc defects.31,32

IL-2 is expressed from a gene on human chromosome 4 or mouse chromosome 3 and is mainly secreted by activated T cells. IL-2 and the heteromultimeric IL-2 receptor (IL-2R) complex (combinations of IL-2Rα/CD25, IL-2Rβ/CD122 and γc) are upregulated on T cells following antigenic or mitogenic stimulation leading to clonal expansion. As such, IL-2 is commonly regarded as an autocrine or paracrine T cell growth factor but it actually has effects on many cell types, such as B cells, NK cells, macrophages and neutrophils.29,33,34The IL-2 knockout mouse exhibits immune dysregulation caused by defects in T cell responsiveness in vitro; however, only delays in normal T cell functionality were found in vivo.35,36 Interestingly, IL-2Rα-37 and IL-2Rβ-deficient38 mice exhibit loss of T cell regulation and autoimmunity, indicating that proper IL-2 signaling may be required to induce regulatory T cells and/or eliminate abnormally activated T cells via the reversal of T cell anergy or apoptosis (programmed cell death) induction, respectively.39

The IL-4 gene is located on human chromosome 5 (along with the IL-3, IL-5, IL-9, IL-13 and granulocyte macrophage colony stimulating factor (GM-CSF) genes) and murine chromosome 11 (along with the IL-3, IL-5, IL-13 and GM-CSF genes). Short or long isoforms of IL-4 can exist arising from alternative splicing.40 IL-4 is produced by activated T cells, mast cells, basophils and NKT cells and targets many cell types, including B cells, T cells, macrophages and a wide variety of hematopoietic and nonhematopoietic cells.29,41 Physiologic signal transduction via IL-4 depends on heterodimerization of the IL-4 receptor α chain (IL-4Ra/CD124), with γc and possibly the IL-13 receptor α chain (IL-13Ra/CD213a1).42 IL-4 is the principal cytokine required by B cells to switch to the production of immunoglobulin (Ig)E antibodies, which mediate immediate hypersensitivity (allergic) reactions and help defend against helminth infections.41 IL-4 also inhibits macrophage activation and most of the effects of IFN-γ on macrophages. However, the most important biological effect of IL-4 with respect to immune modulation is the growth and differentiation of Th2 cells. As described earlier, Th2 cells support humoral immunity and serve to downregulate the inflammatory actions of Th1 cells. Moreover, stimuli that favour IL-4 production early after antigen exposure favour the development of Th2 cells.3 IL-13 is also associated with this subset of T cells.43 Like IL-4, and along with the fact that it maps closely to IL-4 and shares receptor α subunits with IL-4, IL-13 is expressed by activated T cells, induces IgE production by B cells and inhibits inflammatory cytokine production.44 These properties of IL-4 and IL-13 have been convincingly demonstrated in mice lacking the IL-4 or IL-13 gene. 45-48 These mice are deficient in the development and maintenance of Th2 cells.

The remaining γc cytokines, IL-7, IL-9 and IL-15, are potent hematopoietic factors expressed from genes on human chromosome 8 and mouse chromosome 3, human chromosome 5 and mouse chromosome 13, and human chromosome 4 and mouse chromosome 8, respectively. IL-7, expressed by stromal and epithelial cells, stimulates immature B cells, thymocytes and mature T cells via its receptor consisting of the IL-7 receptor α chain (IL-7Rα/CD127) and the γc.49-51 Knocking out IL-7 or IL-7Rα/CD127 causes severe defects in thymic T cell and B cell development consistent with the critical roles that IL-7 and its receptor play in maturation of the immune system.51-56 IL-9 promotes the growth of mast cells, B cells and other T cells and is mainly expressed by activated T cells, especially Th2 cells.29,43,57 Confirming only the role of IL-9 in enhancing mast cells, the recently generated IL-9 knockout mouse exhibits normal T cell (Th2) responses but not characteristic mast cell expansion upon lung challenge.58 IL-15, produced by activated monocytes, epithelial cells, and a variety of tissues, shares biological activities with IL-2 in that it stimulates NK cells, B cells and activated T cells.29,59-61 The IL-15 receptor (IL-15R) consists of combinations of IL-15Rα, IL-2Rβ/CD122 and γc. Similarities in function between IL-2 and IL-15 are partially due to receptor subunit sharing. A recent study, however, provides evidence that IL-2 and IL-15 control different aspects of primary T-cell expansion in vivo. IL-15 is critical for initiating T cell divisions, whereas IL-2 can limit T cell expansion by decreasing γc expression and rendering cells susceptible to apoptosis.62 The α chain ligand specificity and broad cellular expression range of IL-15 allows for differential activity even outside of the immune system.29 IL-15- and IL15Ra-deficient mice were recently generated. Initial studies confirm the role of IL-15 in NK cell stimulation and indicate a role for IL-15 in peripheral CD8 T cell maintenance upon immune challenge.63,64

Common β Chain Cytokines

Cytokines that utilize the common β chain (βc/CDw131) in their receptor comprise the next group of interleukins, namely IL-3, IL-5 and GM-CSF. The genes for IL-3, IL-5 and GM-CSF are closely linked and lie on human chromosome 5 and mouse chromosome 11.65 Like the γc cytokines, these associated (but not particularly homologous at the amino acid sequence level) βc cytokines overlap in biological function because of their common receptor subunit.65 When the βc is mutated, normal hematopoiesis is noted but impaired immune responses can be observed that are most likely due to a loss of responsiveness to IL-5 and GM-CSF, rather than IL-3.66,67

IL-3, originally termed multicolony stimulating factor (multi-CSF), is produced by activated T cells and stimulates both multipotential hematopoietic cells (stem cells) and developmentally committed cells such as granulocytes, macrophages, mast cells, erythroid cells, eosinophils, basophils and megakaryocytes.68-70The human IL-3 receptor consists of CD123 and βc/CDw131. The mouse IL-3 receptor has an additional β chain called βIL-3, the function of which can be compensated for by CD123 if knocked out.67 Knocking out CD123 itself also has little effect on hematopoiesis.71 On the other hand, if IL-3 is knocked out, mast cell and basophil development upon challenge is affected,66 as well as some forms of DTH,72 confirming a role for IL-3 in host defense and expanding hematopoietic effector cells.

IL-5, originally identified as a B cell differentiation factor, is produced mainly by activated T cells (especially Th2 cells) and aids in the growth and differentiation of eosinophils and late-developing B cells.73-75When IL-5 or CDw125 is absent, mice exhibit developmental defects in certain B cells (CD5/B-1 B cells) and a lack of eosinophilia upon parasite challenge.76,77

Lastly, GM-CSF, as its name suggests, was originally found to stimulate granulocytes and macrophages. GM-CSF has since been found to be expressed by many cell types, including macrophages and T cells, and shares many of the functions of IL-3 in stimulating a variety of precursor cells, including macrophages, neutrophils and eosinophils.78-80Interestingly, GM-CSF-deficient mice have normal hematopoietic development but suffer from pulmonary disease perhaps caused by a lack of lung surfactant clearance by alveolar epithelial cells or macrophages.81

IL-6-Like Cytokines

IL-6 is the prototype cytokine representing the next group of interleukins. Most of the members of this group utilize the glycoprotein 130 (gp130) or CD130 receptor. IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), granulocyte colony-stimulating factor (G-CSF) and IL-12 have partially overlapping functions and are key mediators in various immune processes including hematopoiesis and the APR. CD130-deficient mice exhibit embryonic lethality, a finding that appears to be linked to a significant role for CD130-dependent signaling in homeostasis.82

IL-6, with its gene situated on human chromosome 7 and mouse chromosome 5, utilizes the CD130 receptor and the IL-6 receptor α chain (IL-6Ra/CD126). The IL-6Rα/CD126 can exist in a soluble form and serves as an important cofactor by extending the cytokine's half-life.83 IL-6 was originally characterized as a differentiation factor of B cell hybridomas.84,85Producers of IL-6 include fibroblasts, endothelial cells, macrophages, T cells (Th1) and B cells. IL-6 is a primary inducer of fever, hormones, acute phase proteins and T and B cell expansion upon injury and infection.86 It can also act as a cofactor in hematopoiesis by increasing GM-CSF and macrophage colony stimulating factor (M-CSF) expression.87 IL-6-deficent mice exhibit a severely blunted APR following infection or injury,88,89problems in early hematopoiesis and T and B cell function and Th1 development.90 Interestingly, IL-6 can nonetheless act as an anti-inflammatory agent in some instances.91

IL-11, originally identified as a pleiotropic stromal cell-derived cytokine, is encoded on chromosome 19 in humans and chromosome 7 in mice.92,93IL-11 also utilizes the CD130 receptor along with the IL-11 receptor α chain (IL-11Rα). IL-11 is produced by, and has effects on, many hematopoietic and nonhematopoietic cell types.94,95IL-11, like IL-6, is known to stimulate acute phase protein synthesis in the liver.94,95IL-11 also collaborates with other cytokines we have already discussed, such as IL-3, IL-4, IL-7, IL-13 and GM-CSF, to stimulate (by shortening cell-cycle time) the proliferation of hematopoietic stem cells and progenitor cells and induce the differentiation of megakaryocytes.94,95The collaborative nature of IL-11 in vivo may explain why knockout studies have yet to identify a defective phenotype (at least in the hematopoietic compartment) associated with a lack of IL-11 signaling.96 Interestingly, IL-11 could also be an anti-inflammatory mediator as it inhibits macrophage pro-inflammatory cytokine production and can exert protective effects in several disease models.91

LIF is a ligand for CD130 and the LIF receptor (LIFR). LIF is associated with the differentiation of many cell types.91,97,98 In this regard, LIF can both inhibit the differentiation of embryonic stem cells and promote the survival of hematopoietic precursors. LIF can stimulate inflammatory cytokine production. Its expression can be upregulated or downregulated in response to inflammatory cytokines such as IL-1 and TNF or regulatory cytokines such as IL-4, respectively. LIF is therefore often classified as a pro-inflammatory cytokine; however, recent evidence may suggest otherwise in some situations.91 LIF knockout mice display several phenotypes depending on the disease model.91 This may be due to the observation that loss of LIF expression perturbs the establishment of a normal pool of stem cells, but not the terminal differentiation of these cells.99 Unlike IL-6, LIF can also stimulate the hypothalamic-pituitary-adrenal axis in response to stress and disease. This property has been elegantly demonstrated in a recent study of the LIF knockout mouse where mice did not respond to immobilization-induced stress with the normal indicators.100 It is also interesting to note that the genes for LIF and OSM lie in tandem on human chromosome 22 and mouse chromosome 11 and are transcribed in the same orientation.101,102OSM is a very similar cytokine produced mainly by activated macrophages and T cells with inflammatory and growth factor properties.101,102

G-CSF (or colony stimulating factor-3) is produced by fibroblasts and monocytes and stimulates granulocyte progenitor cells and neutrophils.103-105The G-CSF gene is located on human chromosome 17 and mouse chromosome 11 and creates two active polypeptides (differing by only three amino acids) by differential mRNA splicing.103 The G-CSF receptor (G-CSFR) is expressed on multipotential hematopoietic progenitor cells and in cells of the myeloid lineage.104 The importance of G-CSF in granulocyte differentiation and neutrophil development has been verified in G-CSF- and G-CSFR-deficient mice. These mice have lower numbers of circulating neutrophils, a decrease in granulocytic precursors and impaired terminal differentation of granulocytes.106,107

In discussing the IL-6-like cytokines, it bears to mention the heterodimeric cytokine IL-12. IL-12 was originally called NK cell stimulatory factor and can be regarded as a cytokine and soluble receptor complex.108-110The “cytokine” subunit, commonly known as IL-12α or p35, is coded for on human and mouse chromosome 3, shows homology with the IL-6-like cytokines and is not active on its own. The “soluble receptor” subunit, called IL-12β or p40, is coded for on human chromosome 5 and mouse chromosome 11, is a member of the cytokine receptor superfamily with homology to IL-6Ra/CD126 and has activity via the IL-12 receptor (IL-12R/CD212) when partnered with IL-12a. While both soluble subunits are required for biological activity, the two components are differentially regulated.111 IL-12 is produced by APCs and has immunoregulatory effects on NK cells and T cells, two cell types that express the IL-12R.112 IL-12 plays a critical role in cell-mediated immunity by acting as a requisite cytokine in pushing the balance between Th1 cells and Th2 cells towards Th1-type predominance. It is therefore no surprise that IL-12-deficient mice are defective in mounting an IFN-γ- or Th1-mediated immune response and/or respond with default Th2 responses when stimulated with antigen or infected with parasites or bacteria.113-115An interesting note on IL-12 is that a new composite cytokine has been described in mice and humans that consists of a novel a subunit, p19, that combines with IL-12β to form a unique cytokine called IL-23.116 IL-23 has similar biological functions to IL-12 in that it can induce IFN-γ expression by T cells for example, yet it can act distinctly through an unidentified novel receptor subunit.116

IL-10-Like Cytokines

IL-10, IL-19 and IL-20 are members of the next related group of interleukins, those with homology to IL-10. The genes for these cytokines are closely linked on human and mouse chromosome 1.117,118Originally identified as human cytokine synthesis inhibitory factor (CSIF), IL-10 plays a major role in suppressing inflammatory responses. It does this by inhibiting the synthesis of IFN-γ, IL-2, IL-3, TNF-α and GM-CSF by cells such as macrophages and Th1 cells.119,120 However, there is also evidence that IL-10 can act as a stimulator of thymocytes, mast cells and B cells.120 Monocytes and T cells (Th2 cells) are considered to be the main sources of IL-10, although many other cell types can be made to produce IL-10 including B cells, mast cells and keratinocytes.120 The participation of IL-10 in limiting Th1 cell responses and favoring Th2 cell development has been explored in IL-10 knockout mice. Mice that are deficient in IL-10 spontaneously develop chronic intestinal inflammation caused by uncontrolled cytokine production from dysregulated macrophages and Th1 cells.121,122 IL-19 and IL-20 have been recently identified as IL-10 homologues. IL-19 is under patent application and not yet described while IL-20 appears to stimulate keratinocytes via its unique receptor.118


The interferons are a family of cytokines that play a pivotal role in pathogen resistance. There are two types of interferons, type I and II, that signal through different receptors to produce distinct, but overlapping, cellular effects.123 The pleiotropic cytokines IFN-α, originally referred to as leukocyte interferon, and IFN-β, originally referred to as fibroblast interferon, are type I interferons that are secreted by virus-infected cells.124-128Infection by most viruses causes a reaction in the host that includes innate and adaptive immune responses, such as the production of cytokines, increased expression of MHC class I and cytotoxic T cell mobilization. IFN-αand IFN-β, coded for by genes on human chromosome 9 and mouse chromosome 4, appear to be central players in innate immune responses.128 IFN-αand IFN-β also have the unique ability to regulate adaptive T cell responses, perhaps directly by stimulating production of IFN-γ by activated T cells129 or indirectly by inhibiting IL-4-inducible gene expression in monocytes.130 These properties have been verified in knockout mice. Mice lacking the type I IFN receptor (CD118) exhibit impaired antiviral defenses and are deficient in promoting IFN-γ production by T cells.129,131

IFN-γ, also known as immune interferon or type II interferon, is secreted by activated T cells (Th1 cells) and NK cells.123 It was originally identified as an antiviral agent and its gene was mapped to human chromosome 12 and mouse chromosome 10.123,132,133 IFN-γ signals through its own CDw119 receptor and has many biological functions. For example, IFN-γ can stimulate macrophages, increase antigen processing and expression of MHC molecules, promote an Ig class switch to IgG2a antibody secretion, and control the proliferation of transformed cells.123 The immunomodulatory function of IFN-γ, however, has become a major research focus for this cytokine. IFN-γ secretion is the hallmark of proinflammatory Th1 cells but its exact role in T cell subset differentiation remains unclear. Th1 responses are associated with cell-mediated immunity and can best deal with intracellular invaders. Mice with mutations in IFN-γ134 or IFN-γ receptor135 expression show decreased macrophage and NK cell activity and increased susceptibility to many intracellular pathogens and viruses. Cell-mediated immune responses can still develop in IFN-γ knockout mice even though enhancements in Th2-type responses can be observed.136,137As discussed above, IL-12 plays a critical role in eliciting Th1 responses. IFN-γ may act in synergy with IL-12 to accelerate development of the Th1 cell subset and also repress Th2 cells either directly or indirectly.123

Tumor Necrosis Factors

The TNF family is another example of a large group of interrelated cytokines that has stimulated a vast amount of scientific study.138,139Most of this work has centered on the TNF family members' shared properties as cell death effectors.140 The TNF family has been expanding a great deal recently so we have chosen five representative proteins, TNF-α, TNF-β, lymphotoxin (LT)-β, LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T cells) and Fas ligand (FasL)/CD178, to describe in more detail. It appears that all the TNF family members act in trimeric form.138,139Also, with the exception of TNF-β, the TNF ligands are formed as type II transmembrane proteins. Signaling by TNF family members is quite different than other cytokines we have discussed (see reference 138 and 140).

TNF-α, with its gene on human chromosome 6 and mouse chromosome 17 in close linkage to TNF-β, LT-β and MHC genes, is a pro-inflammatory cytokine that was originally identified as a tumour cell killer.141-143TNF-α can be found in a membrane bound or soluble form following proteolytic processing. TNF-α shares a receptor with TNF-β (CD120a, b), which is expressed on virtually all cell types except erythrocytes. TNF-α is produced mainly by activated macrophages, NK cells and T cells (mainly Th1 cells).139 The most potent inducer of TNF-α is lipopolysaccharide (LPS), a microbial agent. TNF-α plays a role in endothelial activation and lymphocyte movement and is one of the crucial mediators in acute and chronic inflammatory conditions, such as autoimmunity, toxic shock and tuberculosis.139,144It is also a direct pyrogen and can indirectly alter hormone and IL-1 secretion to induce fever. Like other members of the TNF family, TNF-α can induce apoptosis (programmed cell death) in some targets.140

TNF-β, also known as LT-α or LT, is derived from T and B cells and shares 30% homology at the amino acid level with TNF-α.142,145TNF-β can exist as a true secreted homotrimeric protein or as a heterotrimeric membrane-associated complex with LT-β.139 Like TNF-α, TNF-β plays a role in endothelial activation, tumour cell killing, apoptosis and mediation of inflammation. While occasional qualitative and quantitative differences have been demonstrated between the actions of TNF-α and TNF-β, the unique functions of TNF-β have not been fully elucidated.138

LT-β is a type II membrane protein that can anchor TNF-β in a heterotrimeric complex.146 LT-β utilizes the LT-β receptor (LT-βR) and the herpes virus entry mediator (HVEM).147 HVEM is a host-encoded receptor that is a member of the tumour necrosis factor receptor family and is exploited by herpes simplex virus (HSV) for entry. The same receptors can also be bound by LIGHT, a recent addition to the TNF family. LIGHT is produced by activated T cells, encoded on chromosome 16 in humans and chromosome 17 in mice and capable of both stimulating T cells and causing apoptosis depending on receptor expression.147 LT-β, however, is produced by activated T and B cells much like TNF-β and is involved in lymph node development.139

As a testament to their important roles as immune mediators, TNF-α, TNF-β and LT-β knockout studies indicate that these three cytokines are required for normal lymphocyte compartmentalization in the spleen (summarized in reference 148). TNF-α- and TNFR1/CD120a-deficient mice lack follicular dendritic cells and fail to form B cell follicles. TNF-β and LT-β knockout mice exhibit similar defects in the spleen and also show impaired development of other lymphoid organs such as lymph nodes and Peyer's patches. These findings may stem from a role for the TNF-α and membrane TNF-β/LT-β heterotrimer in providing developmental cues to stromal cells to produce the chemokines necessary for lymphoid tissue organization.

FasL, newly assigned to CD178, is located on human and mouse chromosome 1.149,150Like TNF-α, FasL can undergo proteolytic processing and exist as a soluble mediator. FasL is produced by T cells and is a key mediator of lymphocyte apoptosis and tolerance when associated with its receptor Fas/CD95. Most types of immune cells, as well as many nonlymphoid tissues, express Fas and/or FasL either constitutively or following activation. The Fas system is therefore very important in immune homeostasis and its powerful role must be tightly regulated or dangerous immune reactions and cancers would occur. Two very useful murine models have allowed a good dissection of the ‘death’ roles Fas and FasL play in immunity.151,152The lpr (lymphoproliferation) mouse has a mutation in Fas that prevents Fas-induced apoptosis and causes complex defects in the B and T cell lymphoid compartments. Similarly, gld (generalized lymphoproliferative disease) mice are mutated in FasL and suffer the same immunoregulatory defects. The role of FasL in killing Fas-expressing T cells is especially evident in the testes, an area of immune privilege that can accept allografts and xenografts, where FasL expression by Sertoli cells is likely responsible for maintaining an immune barrier or immune tolerance.153


The transforming growth factor (TGF)-β family consists of more than 30 members. TGF-β1, 2 and 3 are particularly interesting as they are remarkably multifunctional and indispensable, at least in the mouse. These homodimeric proteins are expressed by and have effects on many cell types. They are involved in development, immune regulation, immune tolerance, carcinogenesis, tissue repair and the generation and differentiation of many types of cells. As such, the TGF-β cytokine family represents an excellent example of a point of integration for multiple information networks, i.e., the immune and developmental programs. These functions cannot be completely outlined here and the reader is directed to several reviews for more details.154-156While the three isoforms of TGF-β are expressed under the control of unique promoters, they share a sequence identity of 70–80%, have similar cell targets and signal through the same serine-threonine kinase receptors (TGF-βR1, 2 and 3) in a manner that is unique from other cytokines.

TGF-β1 is the most abundant form of TGF-β and as such is often plainly referred to as TGF-β. It was originally identified for its ability to promote the growth of fibroblasts and assigned to chromosome 19 in humans and to chromosome 7 in mice.157,158 The human and mouse homologues differ by only one residue in their amino acid sequence. TGF-β1 is produced by every leukocyte lineage and has profound regulatory effects on a myriad of developmental, physiological and immune processes.154 In general, TGF-β1 possesses both pro- and anti-inflammatory activity depending on the presence of other growth factors and the activation or differentiation state of the target cell.154For example, at a site of developing inflammation TGF-β1 can modulate the expression of adhesion molecules, act as a chemoattractant, and orchestrate the immune response by suppressing or activating leukocytes.154,159,160This orchestration by TGF-β1 also applies to the Th cell subset paradigm. TGF-β1 can alter the production of, and response to, cytokines of both Th subsets and can therefore skew Th1 or Th2 immune responses as it sees fit depending on the composition of the inflammatory environment.154 In fact, TGF-β1 secretion is a hallmark of a new candidate regulatory T cell subset called Th3 that also secretes IL-4 and IL-10.161-163With such widespread responsibilities, it is no surprise that TGF-β1 knockout mice exhibit immune dysregulation and succumb to a progressive wasting syndrome shortly after birth.164-166This mortal phenotype is characterized by changes in lymphoid organ architecture, including both the shrinking of the thymus and the swelling of lymph nodes, enhanced proliferation in vivo and defective mitogen responses in vitro. These mice also exhibit massive infiltrations of lymphocytes and macrophages in many organs resembling those found in autoimmune disorders.

TGF-β2, encoded on human and mouse chromosome 1, was originally identified as a suppressor of glioblastoma-derived T cells but is better known for its essential role in the developmental pathways of many tissues.167 Accordingly, TGF-β2-deficient mice exhibit perinatal mortality and a wide array of tissue defects including craniofacial, skeletal, heart, eyes, ears and urogenital anomalies.168 Likewise, TGF-β3, encoded on human chromosome 14 and mouse chromosome 12, appears to have an important role in certain developmental pathways as evidenced by TGF-β3-deficient mice that show severe defects in palate and lung morphogenesis and early death.169-170

Chemokines, their Receptors and their Genes

Chemokines are a family of low molecular weight chemotactic cytokines that regulate leukocyte migration through interactions with seven-transmembrane, rhodopsin-like G protein-coupled receptors.172-174 Chemokines have significant structural homology and overlapping functions and can often bind to more than one receptor. In general, ligand binding results in chemokine receptor activation hallmarked by the phosphorylation of carboxyl-terminal serine/threonine residues, dissociation of heterotrimeric G proteins, generation of inositol trisphosphate, intracellular calcium release and activation of protein kinase C (PKC).175 With additional activation of the Ras and Rho families of guanosine triphosphate (GTP)-binding proteins, chemokine receptors mediate multiple signaling pathways that regulate a wide variety of cellular responses.175

The chemokine field has developed at a rapid pace. This growth has caused classification headaches similar to those experienced by cytokine researchers decades ago. A classification system has been introduced to reduce confusion regarding the nomenclature of these molecules.172,174 Depending on the positions (or in one group the presence) of the first two cysteine residues in the primary structure of these molecules, the chemokine family can be divided into four groups as outlined in Table 2. Unlike the cytokines listed in Table 1, the human chemokines listed in Table 2 do not completely represent the murine chemokines because there are many differences in chemokine terminology between the two species and no matching homologues in some cases (see reference 172 and 174 for more details). The C group of chemokines (lacks cysteines one and three) has been recently described and consists of at least two ligands (XCL), namely lymphotactin/XCL1 and SCM-1β/XCL2, which both bind XCR1.176 Lymphotactin, coded for on human chromosome 1, attracts lymphocytes but not monocytes or neutrophils. The human CC chemokine group (no intervening amino acid) includes at least 27 members (CCL), most of which are encoded on human chromosome 17, that bind at least 10 receptors (CCR). CC chemokine targets include monocytes, T cells, dendritic cells, eosinophils and NK cells. Representative CC chemokines include monocyte chemotactic protein (MCP)-1/CCL2, macrophage inflammatory protein (MIP)-1a/CCL3, MIP-1β/CCL4, regulated upon activation normally T expressed and secreted (RANTES)/CCL5 and eotaxin/CCL11. The CXC group of human chemokines (one amino acid lies between the first two cysteines) includes at least 14 ligands (CXCL). CXC chemokines are mostly encoded on human chromosome 4, bind at least five receptors (CXCR) and mediate mainly neutrophil chemotaxis. The CXC chemokine group can be divided into two main categories based on the presence of the tripeptide Glu-Leu-Arg (ELR) motif preceding the CXC motif. Representative CXC chemokines include IL-8/CXCL8 (ELR), monokine-induced by IFN-γ (MIG)/CXCL9 (nonELR), IFN-γ inducible protein-10 (IP-10)/CXCL10 (nonELR) and stromal cell-derived factor-1 (SDF-1)/CXCL12 (nonELR). Lastly, the sole CX3C chemokine (three intervening amino acids), namely fractalkine/CX3CL1, is encoded on human chromosome 16, binds CX3CR1 and attracts T cells and monocytes but not neutrophils.177

Table 2. Human chemokine and chemokine receptors1.

Table 2

Human chemokine and chemokine receptors1.

Our understanding of the roles of chemokines in physiological and pathological processes has advanced significantly. It has become clear that in addition to wound healing, metastasis, angiogenesis/angiostasis, cell recruitment, lymphoid organ development, and lymphoid trafficking,172,173chemokines are fundamental in mediating innate and adaptive immune responses by their ability to activate cells of the immune system.178-180As with the cytokines, chemokine gene disruption studies have confirmed most of these biological functions. For example, the MIP-1a/CCL3 (a monocyte and T cell chemoattractant) knockout mouse was the first to be generated. While developmentally normal with no apparent lymphoid or myeloid defects, these mice were reduced in their ability to mount an inflammatory response to influenza infection.181 In keeping with the role of eotaxin/CCL11 in attracting eosinophils, eotaxin/CCL11-deficient mice are reduced in their ability to mount eosinophil responses upon antigen challenge.182 SDF-1/CXCL12-mutated mice exhibit a normal T cell compartment but have dramatic defects in B cell lymphopoiesis and myelopoiesis at the level of the bone marrow.183 This result supports the critical role of SDF-1/CXCL12 as a modulator of progenitor cell development in the bone marrow. Knocking out the CXCR2 gene leads to impaired neutrophil migration in response to CXC chemokines, increases in circulating neutrophil numbers, and a dramatic increase in B cells.184,185 Knocking out another CXC chemokine receptor, CXCR5, leads to perturbations in B cell colonization of secondary lymphoid tissues indicating the importance of BCA-1/CXCL13 in B cell coordination.186,187 CCR7-deficient mice exhibit impaired lymphocyte migration, delayed antibody responses, no contact or delayed type hypersensitivity and defects in lymphoid architecture signifying an important role for CCR7 signaling in coordinating primary immune responses.188 Lastly, mutating CCR1, CCR2 or CCR5 in mice impairs monocyte functions such as chemokine-dependent chemotaxis and alters the balance of Th1 or Th2 cytokine responses upon challenge with Th class-specific antigens or pathogens.189-194 With this result, it is interesting to speculate that chemokines play a pivotal role in regulatory and inflammatory responses just like cytokines. For example, chemokines and their receptors have been associated with predominant Th1 or Th2 responses as eluded to earlier.6,195-204This association is evidenced by the linkage of MIP-1a, CXCR3 and CCR5 to Th1-type cells and MCP-1, CCR3, CCR4, and CCR8 to Th2-type cells. Along with cytokine-cytokine receptor interactions, chemokine-chemokine receptor interactions may modulate and stabilize the extent of leukocyte migration to and the nature of inflammation at a developing pathological site. Considering the power of chemokines in recruiting immune cells, these proteins may augment immune responses (helpful or dangerous) via normal immune surveillance mechanisms and may even determine the phenotype of responding cells (e.g., Th1 versus Th2 cells).

Concluding Remarks

As introduced earlier, the immune system is essentially a network supersystem utilizing specialized languages for communication between cells. This chapter focused on only the powerful language of cytokine and chemokine signaling but others exist such as hormone, neurotransmitter, complement and allergic mediator production. At their discretion, immune cells can listen to or send these signals as required to reach cells in the immediate microenvironment or throughout the organism. Just as miscommunication can crash modern electronic networks, the information super-highway of the immune system is not without its vulnerabilities. The knockout models discussed above exemplify the dramatic consequences of man-made alterations to immune network communication. The permanent absence of a particular cytokine at a whole-body level, however, may mask more subtle defects in the role of the conventional signaling component. Similarly, natural defects in communication appear to drive the pathogenesis of autoimmunity. In cases such as this, however, headway is being made in understanding how the immune system communicates and many therapies are being developed that may reset dangerous crashes and return an organism to ‘online’ protective status. A new understanding of the language used by cells of immune system to achieve this protection is emerging and cytokines and chemokines will certainly be at the heart of our progress in communication.


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