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      Prostaglandin I 2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

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          Abstract

          Background

          Prostaglandin I 2 (PGI 2), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI 2 signaling suppressed Th1 and Th2 immune responses, the role of PGI 2 in Th17 differentiation is not known.

          Methodology/Principal Findings

          In mouse CD4 +CD62L + naïve T cell culture, the PGI 2 analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI 2 receptor IP signaling. In mouse bone marrow-derived CD11c + dendritic cells (BMDCs), PGI 2 analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI 2 promotes in vivo Th17 responses.

          Conclusion

          The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI 2 and its analogs are commonly used to treat human pulmonary hypertension.

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          Most cited references31

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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

            We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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              The biological functions of T helper 17 cell effector cytokines in inflammation.

              T helper 17 (Th17) cells belong to a recently identified T helper subset, in addition to the traditional Th1 and Th2 subsets. These cells are characterized as preferential producers of interleukin-17A (IL-17A), IL-17F, IL-21, and IL-22. Th17 cells and their effector cytokines mediate host defensive mechanisms to various infections, especially extracellular bacteria infections, and are involved in the pathogenesis of many autoimmune diseases. The receptors for IL-17 and IL-22 are broadly expressed on various epithelial tissues. The effector cytokines of Th17 cells, therefore, mediate the crucial crosstalk between immune system and tissues, and play indispensable roles in tissue immunity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                10 May 2012
                : 7
                : 5
                : e33518
                Affiliations
                [1 ]Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [2 ]Division of Neurology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [3 ]Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [4 ]Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [5 ]Department of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                Universität Würzburg, Germany
                Author notes

                Conceived and designed the experiments: WZ DCN RSP. Performed the experiments: WZ MMH DRD MTL DCN MGB KG ST HY SY CN SS RMB. Analyzed the data: WZ MMH DRD MTL DCN MGB KG ST HY PW RSP. Contributed reagents/materials/analysis tools: SS RMB GAF. Wrote the paper: WZ DCN GAF RSP.

                Article
                PONE-D-10-03779
                10.1371/journal.pone.0033518
                3349674
                22590492
                ada19237-2f0e-4c4d-9655-d336da332ecc
                Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 18 October 2010
                : 15 February 2012
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Immunology
                Immune Cells
                T Cells
                Immune System
                Cytokines
                Immune Response
                Immunomodulation

                Uncategorized
                Uncategorized

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