Interleukin-1 (IL-1)

Interleukin1-α (IL-1α) and IL-1β , along with TNF-α are key inflammatory cytokines in rheumatoid arthritis (RA),⁹ dermatomyositis and pemphigus.¹⁴ In vitro data suggest that IL-1 is also an important effector cytokine in type 1 diabetes (T1D), through a number of direct (i.e., beta cell toxicity) and indirect means (i.e., by marking beta cells for Fas-dependent destruction by autoreactive cytotoxic T-lymphocytes).⁷ IL-1 is also expressed in the central nervous system (CNS) of animals with experimental autoimmune encephalomyelitis (EAE) and IL-1R antagonsists have been shown to have a moderate therapeutic effect in EAE. IL-1 may contribute to disease severity, rather than to susceptibility in this animal model.⁵

Tumor Necrosis Factor-alpha (TNFα)

TNFα has direct cytotoxic effects on the intestinal mucosa in Crohn's disease and ulcerative colitis but also contributes to the systemic manifestations seen in these diseases. Anti-TNFα antibodies have shown a clear anti-inflammatory effect in patients with Crohn's disease, but the authors raise a note of caution about the long-term effects of TNFα blockade in vivo, particularly in children.¹⁴ There is evidence that some animal models of systemic lupus erythematosus (SLE) produce reduced levels of TNFα. Although the pathogenic role of TNFα in SLE remains unclear, both Lawerys and Houssiau and Nashan and Schwarz point to the observation that RA patients treated with anti-TNFα mAb tend to develop anti-DNA antibodies, and that low TNFα producers have increased susceptibility to develop SLE.^12,13 TNFα appears to have a pathogenic role in the blister lesions of bullous phemphigoid.¹² TNFα plays a critical role in the pathogenesis of RA, and treatment with TNFα and IL-1 blockers offers the highest degree of protection in animal models.^9,11 Furthermore, there is evidence indicating that some TNFα gene variants are markers of RA severity.²

TNFα is also a key cytokine in the development of T1D, contributing to beta cell dysfunction and death, as well as orchestrating antigen-presentation and T-cell activation in situ. The effects of TNFα in vivo, however, are age-dependent and there is evidence that TNFα can also have anti-diabetogenic effects.^7,8 TNFα may be key to the breakdown of tolerance to self antigens in virus-induced diabetes. Interestingly, late expression of TNFα in this model could restore normal beta cell function, possibly by inducing T-cell apoptosis.¹⁰ This dichotomy is a recurrent issue with other cytokines as well.

TNFα has been suggested to play a divergent role in the development of EAE and MS, by causing demyelination and fostering the chronicity of the disease (EAE) or by downregulating the disease process (MS).⁵ Willenborg et al, however, point out the existence of diametrically opposed views on the effects of TNFα in EAE in the literature, ranging from pro-EAE to anti-EAE. Some studies have indicated that EAE can be inhibited by TNFα blockade, whereas studies in humans have suggested that it may increase the number of clinical exacerbations.⁵

TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Chen and Chen discuss the role of TRAIL in autoimmune responses. TRAIL may contribute to suppression of autoimmune inflammation, such as autoimmune arthritis, and thus may have therapeutic value in autoimmune diseases.³

RANK-Ligand (RANKL)

RANKL appears to play a critical role in the bone erosion process that occurs in RA, and RANKL blockade in vivo may have therapeutic value.⁹

TALL-1/BAFF

Lauwerys and Houssiau discuss a role for this tumor necrosis factor family member in SLE. BAFF is a TNF-family member that induces B-cell proliferation by engaging BCMA or TACI receptors on B-cells. Autoantibody production and lupus-like syndromes have been noted in BAFF-transgenic mice, and the levels of TALL/BAFF-1 are elevated in animal models of SLE and human SLE patients.¹³

Interleukin-2 (IL-2)

IL-2- and IL-2R-deficient mice develop an autoimmune syndrome characterized by haemolytic anemia and ulcerative bowel disease. The contribution of IL-2 to autoimmune phenomena may be indirect, i.e., by virtue of the role it plays in T-cell homeostasis.³

Interferon-gamma (IFN-γ)

Peripheral blood mononuclear cells (PBMCs) from SLE patients tend to produce lower levels of IFN-γ than control PBMCs ex vivo. Furthermore, exogenous IFN-γ increases disease severity in some animal models of lupus, and IFN-γ or IFN-αR blockade have beneficial effects.^12,13 Extensive evidence indicates that IFN-γ contributes to the pathogenesis of T1D, but neither IFN-γ nor IFN-γ Rb-deficient NOD mice are resistant to the disease.^7,8 IFN-γ, however, appears to play a critical role in virus-induced diabetes.¹⁰ There is also some evidence suggesting that INF-γ may be necessary for the development of regulatory T-cells and, when administered systemically for example, inhibits insulitis development.⁸ IFN-γ appears to play a downregulating role in EAE (possibly by inducing the production of nitric oxide). On the other hand, IFN-γ blockade appears to alleviate recurrent-relapsing MS (RR-MS).⁵

Interferon-alpha (IFN-α)

IFN-α appears to have a pro-inflammatory effect when expressed as a transgene in beta cells, but is anti-diabetogenic when administered systemically.⁷

Interleukin-6 (IL-6)

IL-6 is elevated in ex vivo organ cultures of inflammed colonic mucosa from both ulcerative colitis and Crohn's disease affected patients, and likely contributes to disease pathogenesis by inhibiting T-cell apoptosis, thereby perpetuating inflammation. Its contribution to pathology is reflected on the observation that IL-6R blockade suppresses colitis in animal models of inflammatory bowel disease.¹⁴ There is also consensus in the literature implicating IL-6 in the development of EAE and possibly MS, but it may have an insignificant effect in disease pathology.⁵

Several lines of experimentation in mice have suggested an important role for IL-6 in the development of islet inflammation, as well as an inhibitory effect on its progression to overt diabetes, perhaps by inducing regulatory Th2 cells.⁷

IL-6 may also play a role in the pathogenesis of SLE and systemic sclerosis (SSc). IL-6 is elevated in sera of SLE and SSc patients and in the cerebrospinal fluid and urine of patients with cerebral lupus and lupus nephritis, respectively. IL-6 may also have a pathogenic role in skin lesions of SLE patients, as discussed extensively by Nashan and Schwarz.¹² IL-6 blockade improves disease outcome in (NZB × NZW) F1 mice, and IL-6 administration exacerbates disease progression.¹² IL-6 may also have a pathogenic role in the blister lesions of bullous phemphigoid.¹²

Interleukin-12 (IL-12)

O'Neil and Steidler note that the small intestine of patients with Crohn's disease contains elevated numbers of IL-12-producing macrophages. These cells are rare in ulcerative colitis lesions and thus may be key to immunopathological differences between these two disorders. IL-12 may contribute to damage of the gut wall by inducing the activation of matrix metalloproteinases. Anti-IL-12 therapy has shown promising results in reversing inflammation in the TNBS-induced model of colitis.¹⁴

IL-12 is indispensable for the induction of EAE, as indicated by studies of IL-12-deficient mice as well as anti-IL-12 mAb-treated animals.⁵

In contrast, there is impaired production of IL-12 in human SLE and murine models of the disease. As discussed by Lauwerys and Houssiau, IL-12 regulates immunoglobulin and autoantibody production and impaired IL-12 secretion may contribute to the pathogenesis of SLE.¹³

IL-12, as a Th1-driving cytokine, appears to play a key role in the initial phases of RA. IL-12 blockade or IL-12 administration inhibit or accelerate the development of RA, respectively.⁹ The role of IL-12 in diabetogenesis is less clear. On the one hand IL-12 administration accelerates diabetes development in NOD mice, and anti-IL-12 treatment is anti-diabetogenic if initiated early, i.e., before development of insulitis. On the other hand, IL-12-deficient NOD mice develop diabetes, implying that Il-12 is dispensable in diabetogenesis.^7,8

Interleukin 15 (IL-15)

IL-15 is increased in ex vivo cultures of Crohn's biopsy samples, but is absent in ulcerative colitis tissue and may play a role in driving local Th1 responses in Crohn's disease.¹⁴ This cytokine is elevated in the synovial fluid of RA patients and may perpetuate the survival of autoreactive T-cells and promote the secretion of arthritogenic cytokines such as TNFα and IL-17. Zheng et al extensively discuss the therapeutic value of IL-15 blockade strategies in autoimmunity, particularly in RA.¹¹

Interleukins-16, -17 and -18 (IL-16, IL-17 and IL-18)

Crohn's disease (but not ulcerative colitis)-affected tissue also contains elevated levels of IL-16. Anti-IL-16 blockade downregulates intestinal mucosal inflammation and damage in the TNBS-induced model of colitis. Crohn's lesions show elevated levels of IL-18 mRNA and active form of the IL-18 protein, which contributes to the Th1-bias seen in Crohn's versus ulcerative colitis disease.¹⁴ IL-16, IL-17 and IL-18 are elevated in serum from SLE and/or SSc patients and may contribute to disease pathogenesis or to some clinical manifestations of the disease process.^12,13 Synovial fluid from RA patients also contains high levels of IL-17 and there is evidence to indicate that it has a direct role in arthritogenesis, possibly by inducing the expression of RANKL.⁹ IL-18, which costimulates induction of IFN-γ by IL-12, may also be involved in RA.⁹ IL-18 appears to prevent the progression of non-destructive to destructive insulitis, but its role in diabetogenesis remains unclear.⁷ Some studies have suggested a role for IL-18 in EAE pathogenesis.⁵

Interleukin-8 (IL-8)/Macrophage Inflammatory Proteins (MIP-1 and MIP-2)

IL-8 is key to recruitment of polymorphonuclear leukocytes to the intestinal mucosa of patients affected with Crohn's disease or ulcerative colitis. Its levels are elevated in lesions from both types of inflammatory bowel disease (IBD).¹⁴ IL-8, along with TNFα, IL-4, IL-5, and IL-13, is also elevated in skin lesions of dermatitis herpetiformis.¹² MIP-1a and MIP-1b have been implicated early in the development of EAE, although there appear to be some differences depending on the inducing antigen (i.e., PLP vs. MBP). MIP-1a blockade with antibodies has been shown to prevent EAE induction, by reducing the recruitment of macrophages. Furthermore, CCR1-deficient mice develop a less severe form of MOG-induced EAE. However, MIP-1a-deficient mice are susceptible to MOG-induced EAE, suggesting a role for MIP-1b.⁶ MIP-2, which is considered to be the functional counterpart of human IL-8, has been detected in the CNS of EAE-affected IFN-γ-deficient Balb/c mice and may be involved in the recruitment of neutrophils to the CNS.⁶

The role of chemokines in diabetes is poorly understood. MIP-1α and MCP-1 appear to play a role in the development of insulitis, and both chemokines can be secreted by autoreactive Th1 cells.⁷ Interestingly, the Idd4 locus, which is associated with diabetes susceptibility in nonobese diabetic (NOD) mice, is linked to the CC chemokine gene cluster. MIP-1α is also expressed in pancreatic islets of a virus-induced diabetes model, at a time when most of the viral particles have already been cleared from the body.¹⁰

Monocyte Chemotactic Proteins (MCPs)

MCP-1 and MCP-3 expression is significantly increased in Chron's and ulcerative colitis lesions and this probably contributes to the recruitment of mononuclear leukocytes to inflammed areas of the intestinal mucosa.¹⁴ MCP-1 may amplify CNS inflammation in PLP-induced EAE, but its role in EAE is unclear, as antibody blocking did not interefere with its induction.⁵ Nevertheless, the eae7 locus, containing genes affording EAE susceptibility, is linked to polymorphisms in TCA-3, MCP-1 and MCP-5.² Some studies have suggested a role for MCP-1 in disease relapses. CCR2 deficiency affords resistance to MOG-induced EAE, possibly by interfering with MCP-1-driven recruitment of macrophages. MCP-1, along with RANTES, MCP-2 and MCP-3, have been detected in MS lesions.⁶

Interferon-γ-Inducing Protein-10 (Crg-2, IP-10), Mig

Christen and von Herrath provide a detailed analysis of chemokine gene expression in the pancreas in a model of virus-induced diabetes. They show that Crg-2 and Mig are expressed soon after virus infection. They are followed, a few days later, by other chemokines, including RANTES, MIP-1α and Eotaxin. Whether any of these chemokines is necessary for diabetes development in this model, however, remains to be determined.¹⁰ IP-10 may be involved in PLP-induced EAE and it has been detected in macrophages/microglia of MS patients, along with other chemokines, including Mig.⁶

Regulated Upon Activation Normally T Expressed and Secreted (RANTES)

RANTES is a pro-inflammatory cytokine with chemotactic properties for T-cells, macrophages, monocytes, eosinophils and NK cells and is overexpressed in the mucosa of Chron's disease and ulcerative colitis patients.¹⁴ RANTES is expressed in pancreatic islets in a virus-induced diabetes model, at a time when most of the viral particles have already been cleared from the body, and can be secreted by autoreactive Th1 cells.¹⁰ RANTES is also expressed in the CNS of EAE-affected animals, but its role in the disease process is less clear than that for other chemokines. However, as pointed out by Babcock and Owens, RANTES blockade does not prevent EAE.⁶

C10, KC/Gro-α

The C10 chemokine has been implicated in the recruitment of macrophages in MOG-induced EAE.⁶ KC/Gro-α is expressed early in the course of EAE and may be responsible for recruiting neutrophils into the CNS.⁶

Interleukin-3 (IL-3)

Meagher et al point out that IL-3 can inhibit diabetogenesis when given to young NOD mice, but whether this cytokine is involved in the disease process is not known.⁷

Interleukin-10 (IL-10)

IL-10-deficient mice develop a form of inflammatory bowel disease that is histologically similar to human IBD. Anti-IL-10 treatment exacerbates mucosal inflammation in the dextran sodium sulphate (DSS) model of colitis, and IL-10 has shown promising results in human clinical trials. IL-10 is increased in the mucosa of IBD patients. Of special note is the efficacy of local delivery of IL-10 using recombinant Lactobacillus lactis in IL-10-deficient mice and in the DSS-induced model of colitis, a strategy pioneered by Steidler and co-workers.¹⁴

Conversely, PBMC from SLE patients produce elevated levels of IL-10 and Lauwerys and Houssiau and Nashan and Schwarz argue that this may play a role in driving auto-antibody production in SLE patients, a point supported by the apparent success of a small clinical trial involving anti-IL-10 administration.^12,13 IL-10 may have an opposite effect in pemphigus vulgaris, as IL-10-deficient mice display increased susceptibility to this disease.¹²

Although the levels of IL-10 are increased in the synovial fluid of RA patients it does not appear to have a pathogenic role. IL-10, however, can prevent collagen-induced arthritis.⁹

The role of IL-10 in diabetogenesis is paradoxical. On the one hand, there is ample evidence for an anti-diabetogenic role of IL-10 in vivo, but on the other hand there is equally convincing evidence in support of just the opposite.^7,8

IL-10 also has a protective effect against EAE, when administered in vivo, and IL-10 blockade increases the incidence and severity of relapses. Most studies, including those involving IL-10-deficient mice, indicate that IL-10 contributes to disease recovery in EAE. The contribution of IL-10 in MS is less clear.⁵

Transforming Growth Factorβ (TGFβ)

TGFβ1 has inhibitory effects on many immune functions and antagonizes the action of a number of pro-inflammatory cytokines, including IFN-γ, IL-1, IL-6, IL-12 and TNFα. As a result, TGFβ1-deficient mice develop systemic inflammatory processes that result in death.³ Local TGFβ expression is increased in IBD. Furthermore, blockade of TGFβ with antibodies exacerbates intestinal inflammation in animal models, and local administration of TGFβ ameliorates the disease process. TGFβ, however, does not appear to play a critical role in IBD pathogenesis.¹⁴ The usefulness of TGFβ therapy in IBD is questionable, as chronic adminstration of TGFβ may result in fibrosis and stenosis and may impair kidney function.⁵ SLE PBMCs appear to secrete lower levels of TGFβ than control PBMCs, and this cytokine may have a pathogenetic role in this disease.¹² TGFβ may play a key role in the fibrosis seen in SSc¹² and in the resolution of inflammatory responses, in general.³ TGFβ has been shown to be a key cytokine in the induction of oral tolerance to autoantigens in a number of models, including experimental colitis, adjuvant arthritis, and EAE,³ and downregulates EAE.⁵ TGFβ has also been shown to have a protective role against type 1 diabetes, by inducing regulatory T-cells, but whether or not this cytokine plays a role in the disease process remains unclear.^7,8

Interferon-β (IFN-β)

Interferon-β1β has been shown to reduce the number and severity of relapses in EAE and RR-MS patients.⁵

Interleukins-4, -11 and -13 (IL-4, IL-11 and IL-13)

IL-4 and IL-13 can downregulate the production of a number of pro-inflammatory mediators involved in IBD, but they can also lead to Th2-mediated forms of the disease. Their production is reduced in the inflamed mucosa of Crohn's disease and/or ulcerative colitis, yet IL-4-producing Th2 cells appear to have a pathogenic role in oxazolone-induced colitis and in the form of IBD that develops in TCRα-deficient mice. Recombinant IL-11, which promotes Th2 responses, ameliorates colitis in HLA-B27 transgenic rats, and colitis induced in rats by TNBS and acetic acid.¹⁴

IL-4 may have a pathogenic role in some models of SLE, but its role in the human disease process is unclear.¹² Lauwerys and Houssiau point out that anti-IL-4 antibodies inhibit autoantibody production and delay the onset of glomerulonephritis in (NZB × NZW) F1 mice.¹³ Likewise, the affected skin of SSc patients exhibits increased levels of IL-4 and may be responsible for some of its clinical manifestations.¹²

IL-4 is absent in the synovial fluid of RA patients. Although overexpression exacerbates inflammation, it appears to protect against cartilage and bone destruction.⁹

Meagher et al and Rabinovitch discuss the role of IL-4 in T1D. There is some evidence for deficient IL-4 production by NK T cells in this autoimmune disorder, and for an anti-diabetogenic effect of IL-4 in animal models using diverse delivery strategies. Administration of IL-11 and IL-13 to young NOD mice can also inhibit diabetogenesis, possibly by reducing the production of pathogenic cytokines, such as TNFα and IFN-γ, and by increasing the production of regulatory cytokines, such as IL-4.^7,8

The role of IL-4 in the pathogenesis of EAE and MS is unclear. IL-4-deficient mice display an increased susceptibility to MOG-induced EAE, and IL-4 can delay the onset and progression of EAE when delivered into the CNS; however, the effects varied depending on the genetic background. Willenborg et al raise the possibility that IL-4 may contribute to disease regulation in MS, as suggested by some studies.⁵ IL-13 has protective effects against EAE in the rat.⁵