Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury

Hofmann, Sigrun R.; Rösen‐Wolff, Angela; Tsokos, George C.; Hedrich, Christian M.

doi:10.1016/j.clim.2012.02.005

Cited by 151 publications

(102 citation statements)

References 110 publications

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“…In various cells, including monocytes/macrophages and T lymphocytes, IL-10 reduces the expression of proinflammatory cytokines, thus inhibiting effector phenotypes (1,2). Some effects of IL-10 on B cells, however, appear contradictory.…”

Section: Discussionmentioning

confidence: 99%

“…I L-10 is an immune-regulatory cytokine that plays a central role in innate and adaptive immune responses (1,2). Immune cells ubiquitously express IL-10 with T and B cells, natural killer (NK) cells, mast cells, eosinophils, dendritic cells, and monocytes/ macrophages as major sources.…”

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confidence: 99%

“…Autoantibody production by B cells and plasma cells, the accumulation of immune complexes in tissues, and excessive cytokine production contribute to autoimmune pathology (4). A growing body of literature suggests increased IL-10/IL-10 receptor interactions contributing to SLE (1)(2)(3). Studies document increased IL-10 serum levels in SLE patients and lupus-prone mice correlating with disease activity, antibody production, and organ damage (2,3,(5)(6)(7)(8)(9).…”

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confidence: 99%

“…IL-10 expression is controlled on the transcriptional and posttranscriptional levels. IL10 is trans-regulated by a number of factors, including signal transducer and activator of transcription molecules Stat1, Stat3, Stat4, and Stat5 (1,2). We and others demonstrated that, in addition to the IL10 promoter, an enhancer in the fourth intron, referred to as intronic Stat-responsive element (I-SRE), regulates IL-10 in murine NK cells (through Stat4) and human T cells (through Stat5) (10,11).…”

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confidence: 99%

“…Conversely, IL-10 promotes B-cell differentiation, proliferation, survival, and antibody production. Thus, IL-10 has been implicated in the pathophysiology of autoimmune disorders (1)(2)(3).…”

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confidence: 99%

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Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

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

154

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The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

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

154

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Interleukins

Meager

Wadhwa

2013

Encyclopedia of Life Sciences

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The interleukins are a major class of biologically active protein mediators, known as cytokines, that following release from activated cells bind to specific cell surface receptors to induce growth and differentiating functions in target cells. Extensive studies into their genes, structures, receptors, signal transduction pathways and activities in experimental cell cultures have provided considerable knowledge leading to their molecular and biological characterisation. Fundamental findings are that they are mostly pleiotropic mediators, that is, act on more than one cell type or at different stages of cellular development, and stimulate multiple activities, especially where acting in combinations of two or more interleukins. Their production as essentially pure recombinant proteins has enabled studies in experimental model systems to determine whether their activities could be of clinical benefit, or harmful. Subsequently, several interleukins and their antagonists have been evaluated for clinical efficacy and safety in clinical studies, and have yielded promising, though not fully effective, therapeutic treatments for patients with cancer and autoinflammatory diseases. In this article, the molecular characteristics of interleukins, their cognate receptors and intracellular signalling pathways, their biological activities and their potential clinical uses are briefly described. Key Concepts: Interleukins are a broad class of biologically active proteins with hormone‐like actions that regulate the development, differentiation and functions of cells of the immune and haematopoietic systems. The activities of interleukins are mediated via cell surface receptors. Binding of interleukins to receptors triggers gene induction via the activation of intracellular signal transduction pathways. Interleukins exhibit complex biological interactions, both among themselves and with other molecular mediators, in vivo . The proinflammatory and immune‐stimulatory activities of interleukins are essential for host defence against pathogens. Interleukins can be ‘two‐edged swords’, being largely beneficial to the host at low concentrations but deleterious and toxic at high concentrations. The biological properties of interleukins have suggested their potential for development as therapeutic drugs (biopharmaceuticals) against infections and chronic diseases, such as cancer, but so far only a few have proved clinically useful. Antibody and receptor antagonists of interleukins are showing promise for the treatment of autoinflammatory and autoimmune diseases, such as irritable bowel disorders and RA.

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