The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS)

doi:10.1016/S1359-6101(02)00025-4

Cytokine & Growth Factor Reviews

Volume 13, Issues 4–5, August–October 2002, Pages 403-412

https://doi.org/10.1016/S1359-6101(02)00025-4 Get rights and content

Abstract

Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a crucial role in inflammatory and immune reactions. It has potent anti-inflammatory and immunosuppressive activities on myeloid cell functions which forms a solid basis for its use in acute and chronic inflammatory diseases. Here, we discuss the role of IL-10 in autoimmune diseases and examine its beneficial effects in cellular-based autoimmune diseases such as multiple sclerosis (MS) or its involvement in humoral-based autoimmune diseases such as systemic lupus erythematosus (SLE). Inhibition of the immune stimulatory activities of IL-10 may provide novel approaches in the treatment of humoral autoimmune diseases, infectious diseases and cancer.

Introduction

Interleukin-10 (IL-10) is a homodimeric cytokine. Through the interaction with its heterodimeric receptor complex it modulates the biological activities of immune cells, keratinocytes and endothelial cells. Crucial to the understanding of IL-10 biology are the effects of this cytokine on the function of myeloid cells including monocytes, dendritic cells and macrophages. IL-10 strongly inhibits the activation of these cells, resulting in a reduced production of pro-inflammatory mediators, including cytokines and chemokines, adhesion and accessory molecules, and leads to diminished T cell stimulation [1], [2], [3]. These activities form an important component of the anti-inflammatory and immunosuppressive effects of IL-10. The inhibitory effects of IL-10 on the pro-inflammatory function of granulocytes, T helper 1 cells, NK cells and endothelial cells further contribute to its central role as “dampener” of inflammation [4], [5], [6], [7], [8], [9], [10].

IL-10 also exerts immune stimulatory effects on select cell types and these activities may be more restricted to certain species. Early on, IL-10 was shown to exhibit growth factor activity for mouse mast cells and thymocytes [11], [12]. Furthermore, IL-10 induces recruitment, proliferation and cytotoxic activity of CD8⁺ T cells in both mouse and human [13], [14], [15], [16]. A clear species difference is observed with respect to the responsiveness of B cells to IL-10. Although IL-10 enhanced viability and survival of mouse resting B cells and stimulates the proliferation of B1 B cells, the activities of IL-10 on human B cells are much more pronounced [17], [18]. IL-10 is a potent cofactor for the proliferation of human B cells activated by anti-IgM, SAC or CD40 cross-linking [19], [20]. In addition, IL-10 enhances immunoglobulin production by naı̈ve and committed B cells and acts as a switch factor for IgG1, IgG3 and IgA production. Long term culture of activated B cells in the presence of IL-10 leads to differentiation of B cells into plasma cells [21]. Prolonged exposure to IL-10 also leads to modulation of the phenotype and function of monocytes and T cells. As mentioned, IL-10 strongly inhibits the pro-inflammatory activities of monocytes, but it enhances the expression of CD64 (FcγRI) and CD163, a scavenger receptor, thereby leading to the differentiation of macrophage-like cells that contribute to clearance of infection via enhanced phagocytosis [22], [23], [24], [25]. Finally, IL-10 may be involved in the generation of peripheral tolerance though the induction of T cell anergy and its role in the differentiation of at least one type of regulatory T cell [26], [27], [28] (Fig. 1).

It is clear from these varied and profound activities of IL-10 that it is involved or affects many aspects of human disease, especially those diseases that have an immunological component or etiology. Indeed many studies have shown a role of IL-10 in infectious diseases, acute and chronic inflammatory diseases, cancer, transplantation and autoimmune diseases [29]. The anti-inflammatory effects of IL-10 have led to numerous in vitro and in vivo studies demonstrating beneficial effects of IL-10 in models of sepsis [30], endotoxemia [31], [32], pancreatitis [33], uveitis [34], keratitis [35], hepatitis [36] and lung [37], [38], [39], brain [40] or spinal cord injury [41]. IL-10 administration also reduced inflammation in animal models of rheumatoid arthritis [42], [43] and inflammatory bowel disease [44], [45] and showed some efficacy in phases I and II clinical trials for these indications [46], [47]. An extensive review on IL-10 biology and its effects on these various diseases has been recently published [29]. Therefore, we will focus here on the role of IL-10 in two autoimmune diseases, SLE and multiple sclerosis (MS) with its murine model experimental autoimmune encephalomyelitis (EAE).

Section snippets

IL-10 and systemic lupus erythematosus

SLE is a multi-organ autoimmune disease characterized by B cell hyperactivity leading to excessive autoantibody production. SLE patients have high levels of circulating autoantibodies against a number of nuclear antigens including dsDNA and ribonucleoproteins. Tissue damage is triggered by an inflammatory response to immune complex deposition and is widespread. The primary cause of morbidity and mortality is glomerulonephritis which develops in about 60% of patients. Upon discovery that IL-10

The role of IL-10 in mouse models of SLE

The suspicion that IL-10 may play a role in SLE was boosted early on by a study in lupus prone NZB/W F1 mice [48]. NZB/W F1 mice spontaneously develop a lupus-like disease characterized by anti-dsDNA autoantibodies and glomerulonephritis [49]. Ishida and coworkers found that treatment of NZB/W F1 mice from birth with anti-IL-10 mAb improved 34-week survival from about 10 to 80%. This improved survival correlated with decreased anti-dsDNA autoantibodies, decreased proteinuria, and decreased

The role of IL-10 in human SLE: production of IL-10 by peripheral blood mononuclear cells (PBMCs)

Llorente et al. published the first paper describing IL-10 production by PBMCs from SLE patients [50]. This study on 47 patients, with clinical conditions ranging from inactive to severe, stands out in that none of the patients were on corticosteroids, non-steroidal anti-inflammatory drugs, or other immunosuppressive drugs. By RT-PCR, PBMCs from 34 of 47 SLE patients were positive for IL-10 transcripts, while only 1 of 34 healthy controls was positive. When PBMCs from 20 of these patients (19

The role IL-10 in human SLE: correlation of serum IL-10 levels and disease activity

Actual measurements of circulating serum IL-10 levels might be expected to give a clearer picture of disease association for two reasons. First, serum IL-10 reflects IL-10 production from many sources, including PBMCs, cells in tissues such as macrophages and certain epithelial cells, and viruses such as EBV. Second, measurement of serum IL-10 circumvents the variability inherent in studies involving ex vivo manipulation of cells. Indeed, levels of IL-10 in the serum of SLE patients have

The role of IL-10 in human SLE: IL-10 gene polymorphisms

The above studies show a correlation of high IL-10 levels with SLE, but do not answer the question of whether high levels of IL-10 are simply a byproduct of SLE and flares, or whether IL-10 plays a role in the disease process. There are some clues, however, that IL-10 may predispose to SLE. Studies showing that healthy relatives of SLE patients have increased numbers of IL-10-producing PBMCs [65] or increased levels of IL-10 production by PBMCs [52], [96] imply that part of the hereditary

The role of IL-10 in human SLE: B cell activation

One predicted role of IL-10 in SLE is its ability to promote B cell differentiation and autoantibody production. IL-10 is a cofactor for these activities and requires B cell activation via the B cell receptor or costimulatory molecules such as CD40. Due to the constant presence of nuclear antigens such as dsDNA, and antibodies directed against them, B cells in SLE patients are continuously primed for costimulation by IL-10. One might then expect decreased autoantibody production upon blocking

IL-10 and experimental autoimmune encephalomyelitis

EAE is a myelin-antigen induced central nervous system (CNS) inflammation mediated by self-antigen specific T cells [121]. These autoreactive T cells invade the CNS, and together with bone-marrow-derived inflammatory macrophages, produce encephalomyelitis and focal demyelinating lesions. Primary CNS demyelination, and the relapsing course of the disease in some model systems, provide the basis for the study of EAE as a model of MS, a prevalent human autoimmune-mediated demyelinating disease.

Efficacy of IL-10 treatment in EAE: importance of route of administration

Direct evidence for IL-10 regulation of CNS autoimmunity was provided by studies showing that neutralization of endogenous IL-10 increased the severity and incidence of EAE [136] and that the disease was more severe in IL-10 deficient compared to wild-type mice [137], [138], [139]. Furthermore, FVB × SJL F1 mice expressing murine IL-10 under the T cell-specific CD2 promoter were resistant to EAE induced by PLP immunization [137]. Similarly, transgenic mice that express human IL-10 (hIL-10)

Conclusions

The concept of cytokines acting as a two edged sword is well established. The balance between beneficial and deleterious effects of cytokine therapy depends on the context of the challenge that the immune system faces. In the case of IL-10, administration of this cytokine is beneficial in situations where excessive inflammatory responses of either Th1 or Th2 type lead to pathology. However, one can have too much of a good thing. Overproduction or inappropriate production of IL-10 can lead to

Acknowledgements

DNAX Research Inc. is supported by Schering-Plough Pharmaceutical Corporation. The authors would like to thank Drs. R.B. Fick, K.W. Moore and J.S. Sedgwick for their review and helpful comments.

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SurveyThe role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS)

Abstract

Introduction

Section snippets

IL-10 and systemic lupus erythematosus

The role of IL-10 in mouse models of SLE

The role of IL-10 in human SLE: production of IL-10 by peripheral blood mononuclear cells (PBMCs)

The role IL-10 in human SLE: correlation of serum IL-10 levels and disease activity

The role of IL-10 in human SLE: IL-10 gene polymorphisms

The role of IL-10 in human SLE: B cell activation

IL-10 and experimental autoimmune encephalomyelitis

Efficacy of IL-10 treatment in EAE: importance of route of administration

Conclusions

Acknowledgements

Gastroenterology

Cell

Res. Immunol.

Rheum. Dis. Clin. North Am.

Cytokine

Cytokine

J. Autoimmun.

Transfus. Sci.

IL-10 inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

J. Exp. Med.

Interleukin-10 inhibits T cell alloreaction induced by human dendritic cells

Int. Immunol.

Interleukin-10 inhibits the primary allogeneic T cell response to human epidermal Langerhans cells

Eur. J. Immunol.

Interleukin-10 (IL-10) inhibits the release of pro-inflammatory cytokines from human polymorphonuclear leukocytes: evidence for an autocrine role of tumor necrosis factor and IL-1β in mediating the production of IL-8 triggered by lipopolysaccharide

J. Exp. Med.

Regulation of neutrophil-derived chemokine expression by IL-10

J. Immunol.

IL-10 and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II MHC expression

J. Exp. Med.

IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells

J. Immunol.

Differential effects of IL-4 and IL-10 on IL-2-induced IFN-γ synthesis and lymphokine-activated killer activity

Int. Immunol.

Regulation of the production of the RANTES chemokine by endothelial cells: synergistic induction by IFN-γ plus TNF-α and inhibition by IL-4 and IL-13

J. Immunol.

A critical role for monocytes and CD14 in endotoxin-induced endothelial cell activation

J. Exp. Med.

Interleukin-10: a novel stimulatory factor for mast cells and their progenitors

J. Exp. Med.

IL-10: a novel cytokine growth cofactor for mature and immature T cells

J. Immunol.

Human IL-10 is a chemoattractant for CD8+ T lymphocytes and an inhibitor of IL-8-induced CD4+ T lymphocyte migration

J. Immunol.

Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells

J. Immunol.

Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8+ cytotoxic T lymphocytes

J. Virol.

IL-10: a novel cytotoxic T cell differentiation factor

J. Immunol.

Ly-1 B (B1) cells are the main source of B cell-derived interleukin-10

Eur. J. Immunol.

Interleukin-10 (IL-10), a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells

J. Exp. Med.

IL-10 is a potent growth and differentiation factor for activated human B lymphocytes

Proc. Natl. Acad. Sci. U.S.A.

Human B cell precursors proliferate and express CD23 after CD40 ligation

J. Exp. Med.

Long-term cultured CD40-activated B lymphocytes differentiate into plasma cells in response to IL-10 but not IL-4

Int. Immunol.

Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes: comparison with IL-4 and modulation by IFN-γ or IL-10

J. Immunol.

IL-10 stimulates monocyte FcγR surface expression and cytotoxic activity: distinct regulation of antibody-dependent cellular cytotoxicity by IFN-γ, IL-4, and IL-10

J Immunol.

IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages

Eur. J. Immunol.

Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and anti-inflammatory stimuli

J. Leucoc. Biol.

Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells

J. Exp. Med.

A CD4+ T cell subset inhibits antigen-specific T cell responses and prevents colitis

Nature

Type 1 T regulatory cells

Immunol. Rev.

Interleukin-10 and the interleukin-10 receptor

Annu. Rev. Immunol.

Survey
The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS)

Human IL-10 is a chemoattractant for CD8⁺ T lymphocytes and an inhibitor of IL-8-induced CD4⁺ T lymphocyte migration

Inhibitory and stimulatory effects of IL-10 on human CD8⁺ T cells

Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8⁺ cytotoxic T lymphocytes

Interleukin-10 induces a long-term antigen-specific anergic state in human CD4⁺ T cells

A CD4⁺ T cell subset inhibits antigen-specific T cell responses and prevents colitis