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      The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges

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          Abstract

          Inflammation is a fundamental response of the immune system whose successful termination involves the elimination of the invading pathogens, the resolution of inflammation and the repair of the local damaged tissue. In this context, the interleukin 10 (IL-10)-mediated anti-inflammatory response (AIR) represents an essential homeostatic mechanism that controls the degree and duration of inflammation. Here, we review recent work on the mechanistic characterization of the IL-10-mediated AIR on multiple levels: from the cataloguing of the in vivo genomic targets of STAT3 (the transcription factor downstream of IL-10) to the identification of specific co-factors that endow STAT3 with genomic-binding specificity, and how genomic and computational methods are being used to elucidate the regulatory mechanisms of this essential physiological response in macrophages.

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          Most cited references52

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            Biology of interleukin-10.

            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. Copyright © 2010 Elsevier Ltd. All rights reserved.
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              Latent enhancers activated by stimulation in differentiated cells.

              According to current models, once the cell has reached terminal differentiation, the enhancer repertoire is completely established and maintained by cooperatively acting lineage-specific transcription factors (TFs). TFs activated by extracellular stimuli operate within this predetermined repertoire, landing close to where master regulators are constitutively bound. Here, we describe latent enhancers, defined as regions of the genome that in terminally differentiated cells are unbound by TFs and lack the histone marks characteristic of enhancers but acquire these features in response to stimulation. Macrophage stimulation caused sequential binding of stimulus-activated and lineage-determining TFs to these regions, enabling deposition of enhancer marks. Once unveiled, many of these enhancers did not return to a latent state when stimulation ceased; instead, they persisted and mediated a faster and stronger response upon restimulation. We suggest that stimulus-specific expansion of the cis-regulatory repertoire provides an epigenomic memory of the exposure to environmental agents. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Brief Funct Genomics
                Brief Funct Genomics
                bfgp
                bfgp
                Briefings in Functional Genomics
                Oxford University Press
                2041-2649
                2041-2657
                November 2013
                12 August 2013
                12 August 2013
                : 12
                : 6 , Special Issue: Functional Genomics of the immune system
                : 489-498
                Author notes
                Corresponding author. D. Miranda-Saavedra, Bioinformatics and Genomics Laboratory, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, 565-0871 Osaka, Japan. Tel.: +81 6 6879 4269; Fax: +81 6 6879 4272; E-mail: diego@ 123456ifrec.osaka-u.ac.jp
                Article
                elt028
                10.1093/bfgp/elt028
                3838198
                23943603
                cd32d8de-69ca-48b2-b151-29501f317a09
                © The Author 2013. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 10
                Categories
                Papers

                Genetics
                il-10,jak1,stat3,anti-inflammatory response,macrophages,transcriptional regulatory modules,bioinformatics

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