Biology of interleukin-10

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Abstract

Interleukin (IL)-10 is the most important cytokine with anti-inflammatory properties besides TGF-β and IL-35. It is produced by activated immune cells, in particular monocytes/macrophages and T cell subsets including Tr1, Treg, and Th1 cells. IL-10 acts through a transmembrane receptor complex, which is composed of IL-10R1 and IL-10R2, and regulates the functions of many different immune cells. In monocytes/macrophages, IL-10 diminishes the production of inflammatory mediators and inhibits antigen presentation, although it enhances their uptake of antigens. Additionally, IL-10 plays an important role in the biology of B cells and T cells. The special physiological relevance of this cytokine lies in the prevention and limitation of over-whelming specific and unspecific immune reactions and, in consequence, of tissue damage. At the same time, IL-10 strengthens the “scavenger”-function and contributes to induced tolerance. This review provides an overview about the cellular sources, molecular mechanisms, effects, and biological role of IL-10.

Introduction

In 1989, Mosmann and co-workers described a novel immune mediator that is secreted by mouse type 2 T-helper cell clones (Th2) and inhibits the synthesis of interleukin (IL)-2 and interferon (IFN)-γ in Th1 cell clones [1]. Originally named “cytokine synthesis inhibitory factor” (CSIF), this mediator was accepted as “IL-10” in the everyday cytokine nomenclature. In the 21 years since its discovery, numerous groups have intensively investigated the biology of IL-10.

Section snippets

The IL-10 gene and protein

The gene encoding human IL-10 is located on chromosome 1. It covers a total of 5.1 kb pairs and comprises five exons [2]. A large number of polymorphisms [primarily single nucleotide polymorphisms (SNPs)] have been identified in the IL-10 gene promoter. Some evidence exists that certain of these polymorphisms are associated with differential expression of IL-10 in vitro, and a number of studies have investigated associations between IL-10 polymorphisms and various diseases (see below). The IL-10

Cellular sources of IL-10

Today it is known that the ability to synthesize IL-10 is not limited to certain T cell subsets, but is a characteristic of almost all leukocytes [15]. Very important sources in vivo appear to be mainly monocytes and macrophages as well as Th cells [16], [17], [18], [19]. Moreover, dendritic cells, B cells, cytotoxic T cells, γδ T cells, NK cells, mast cells, as well as neutrophilic and eosinophilic granulocytes synthesize IL-10 [20], [21], [22], [23], [24], [25], [26], [27], [28]. Which of

The IL-10 receptor

IL-10's pleiotropic activities are mediated by a specific cell surface receptor complex. This IL-10 receptor (IL-10R) is composed of two different chains, IL-10R1 and IL-10R2 (Fig. 2). Both chains belong to the class II cytokine receptor family (CRF2). CRF2 members are usually transmembrane glycoproteins, whose extracellular domains typically consist of about 210 amino acids, form two fibronectin type III domains, and have several conserved amino acid positions that are important for their

Biological effects of IL-10

The biological effects of IL-10 are incredibly multifaceted and were intensively investigated in the last years. In doing this, the effects on various cell populations including thymocytes, T cells, B cells, NK cells, monocytes, macrophages, mast cells, as well as neutrophilic and eosinophilic granulocytes were illuminated. According to the latest knowledge, it appears that above all monocytes/macrophages are the main target cells of the inhibitory IL-10 effects. Interestingly, the IL-10R

Molecular basis of IL-10's immunosuppressive effects

The exact molecular mechanisms of immunosuppressive effects of IL-10 on APCs (the inhibition of cytokine production and antigen presentation) and T cells (the suppression of cytokine production and proliferation) are still a matter of debate despite a long research activity in this field.

There is however general agreement that STAT3 activation by IL-10 receptor engagement is essential for the anti-inflammatory effects of IL-10 in cells of myeloid origin. This was demonstrated most convincingly

Role of IL-10 in immune-mediated diseases

There are numerous investigations that describe an important role of IL-10 in the pathogenesis of various diseases. These diseases can be subdivided into:

  • (a)

    Diseases with relative or absolute IL-10 over-production and

  • (b)

    Diseases with a relative or absolute IL-10 deficiency.

In diseases with an IL-10 over-production, undesired immunosuppressive effects of IL-10 and the growth of some tumors can be observed. Lupus erythematosus, EBV-associated lymphomas, and skin malignomas such as melanoma belong to

Biological relevance of IL-10

The biological relevance of IL-10 is better understandable if the timeline of released cytokines after cell activation is kept in mind. IL-10 is a rather late cytokine being produced after the pro-inflammatory mediators. Thereby, it has a special physiological significance in limiting and preventing an excessive immune response and in limiting collateral damage. Concurrently, it strengthens the “scavenger” functions of the immune system which is important after a conflict with antigens, and it

Acknowledgments

The authors thank Elisabeth Wallace and Brigitte Ketel for the assistance.

Robert Sabat (born in 1969 in Poland) is the director of the Molecular Immunopathology interdisciplinary department at the University Hospital Charité in Berlin, Germany. In 1995, he graduated from the Humboldt University medical school in Berlin, Germany. Subsequently, he completed his medical internship and residency at the Institute for Medical Immunology, University Hospital Charité, Berlin. His medical doctorate thesis focused on interleukin-10. In 1999, he went to the Department of

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    Robert Sabat (born in 1969 in Poland) is the director of the Molecular Immunopathology interdisciplinary department at the University Hospital Charité in Berlin, Germany. In 1995, he graduated from the Humboldt University medical school in Berlin, Germany. Subsequently, he completed his medical internship and residency at the Institute for Medical Immunology, University Hospital Charité, Berlin. His medical doctorate thesis focused on interleukin-10. In 1999, he went to the Department of Dermatology at Schering Inc. to work as a research group head for three years. During this time, he directed two projects: “Molecular mechanisms of the immunosuppressive effects of interleukin-10” and “New members of the cytokine receptor family class 2”. The Molecular Immunopathology department of the Charité Berlin, which he has been charged with since 2003, links clinical research at the Department of Dermatology with basic science at the Institute for Medical Immunology. His main research interests lie in: the function of novel interleukin-10 related cytokines and the pathogenesis of chronic inflammatory diseases.

    Gerald Grütz studied Biochemistry/Molecular Biology at the Humboldt University in Berlin. He obtained his PhD in 1994 after working at the Institute of Medical Immunology of the University Hospital Charité in Berlin under supervision of Prof. von Baehr and Prof. Volk in the area of antibody engineering against pro-inflammatory cytokines for therapeutic approaches in septic shock. He moved then to work as a postdoc with Dr. Rabbitts at the PNAC department of the MRC-LMB in Cambridge (UK) for 5 years. His focus there was the molecular basis of acute T cell leukaemia caused by the transcription factor LMO2. His research interest returned back to Immunology when he started his own group at the Institute of Medical Immunology at Charité from 1998. There he was working on gaining insight into the cellular and molecular mechanism of inflammation and cytokine regulation by the anti-inflammatory cytokines IL-10 and TGF-β. Since the beginning of 2010 he is heading the Department of Biocompatibility at the Biomaterial Research Centre of the GKSS in Teltow. There he is studying the impact of biomaterials designed for regenerative therapeutic approaches on the immune system.

    Katarzyna Warszawska obtained her BSc and MSc in Biology from the University of Warsaw, Poland. For the last 4 years she has been working on her Ph.D. thesis in the Interdisciplinary Department of Molecular Immunopathology at the Charité University Hospital, Berlin. Her work is concerned with the research on the determination of the role of IL-22 in inflammatory conditions, like skin diseases and various infection models.

    Stefan Kirsch studied Biotechnology at the University of Applied Sciences Berlin. After receiving his diploma in 2004 he worked for Biosyntan GmbH. Since 2007 he is a PhD student in the Interdisciplinary group of Molecular Immunopathology at the University Hospital Charité, Berlin.

    Ellen Witte is a research fellow in the Interdisciplinary Department of Molecular Immunopathology directed by Robert Sabat M.D. (Charité University Hospital). She received her diploma (5-year degree) in Biology from the Humboldt University in Berlin, Germany. She just has completed her Ph.D. work that dealt with the biological significance of the cytokine IL-22 and its natural inhibitor IL-22BP in psoriasis and Crohn's disease.

    Kerstin Wolk is an immunologist and works as a research team head in the Interdisciplinary Molecular Immunopathology Department at the University Hospital Charité in Berlin, Germany. She obtained both a diploma (5-year degree) in Biopharmacology from the University of Greifswald, Germany, and a diploma in Environmental Toxicology from the University of Metz, France. She later graduated with a Ph.D. from the University of Greifswald (supervisors: Reinhard Walter, M.D., Ph.D., Institute of Biochemistry of the University Hospital Greifswald and Hans-Dieter Volk, M.D., Ph.D., Institute of Medical Immunology of the University Hospital Charité, Berlin, Germany). For her thesis she worked on endotoxin tolerance as a model of post-inflammatory immunodepression in critically ill patients. Afterwards, she accepted a postdoctoral position at Schering, Inc., Berlin, in the Department of Dermatology. With her research team in the Molecular Immunopathology Department (director: Robert Sabat) at the Charité in Berlin, she currently investigates the role of interleukin (IL)-10 family cytokines, such as IL-22 and IL-28IL-29.

    Jens Geginat (born 1968 in Berlin, Germany) is heading the Autoimmunity Program at the Istituto Nazionale di Genetica Molecolare (INGM) in Milan, Italy. He graduated in Biochemistry at the Free University of Berlin in 1994 and did the experimental work of his PhD at the Scientific Institute S. Raffaele DiBit in Milan with Ruggero Pardi. In 1999 he joined the group of Antonio Lanzavecchia at the Basel Institute for Immunology and in 2000 he moved to the Research Institute for Biomedicine (IRB) in Bellinzona, Switzerland. In 2006 he became a Junior Group Leader in Berlin of the University Hospital Charité at the German Rheumatology Research Centre (DRFZ) headed by Andreas Radbruch. In 2009 he was appointed as a Program Leader at INGM, whose mission is to perform translational research in Biomedicine. In 2010 he obtained his Habilitation in Immunology at the Charitè. His main research interest is human T cell biology, in particular the generation and maintenance of memory T cells and more recently the characterization of regulatory T cell subsets.

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    Both authors contributed equally to this work.

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