title: Nitric oxide enhances Th9 cell differentiation and airway inflammation.
abstract: Th9 cells protect hosts against helminthic infection but also mediate allergic disease. Here we show that nitric oxide (NO) promotes Th9 cell polarization of murine and human CD4(+) T cells. NO de-represses the tumour suppressor gene p53 via nitrosylation of Mdm2. NO also increases p53-mediated IL-2 production, STAT5 phosphorylation and IRF4 expression, all essential for Th9 polarization. NO also increases the expression of TGFβR and IL-4R, pivotal to Th9 polarization. OVA-sensitized mice treated with an NO donor developed more severe airway inflammation. Transferred Th9 cells induced airway inflammation, which was exacerbated by NO and blocked by anti-IL-9 antibody. Nos2(-/-) mice had less Th9 cells and developed attenuated eosinophilia during OVA-induced airway inflammation compared with wild-type mice. Our data demonstrate that NO is an important endogenous inducer of Th9 cells and provide a hitherto unrecognized mechanism for NO-mediated airway inflammation via the expansion of Th9 cells.
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Wanda
authors.initials: W
authors.lastname: Niedbala
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Anne-Gaelle
authors.initials: AG
authors.lastname: Besnard
authors.affiliation: 1] Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK [2] Inflammation and Pain Group, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Daniele Carvalho
authors.initials: DC
authors.lastname: Nascimento
authors.affiliation: Inflammation and Pain Group, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Paula Barbim
authors.initials: PB
authors.lastname: Donate
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Fabiane
authors.initials: F
authors.lastname: Sonego
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Edwin
authors.initials: E
authors.lastname: Yip
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Guabiraba
authors.affiliation: Cell Biology Group, German Rheumatism Research Center, a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Sandra Y
authors.initials: SY
authors.lastname: Fukada
authors.affiliation: Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Salmond
authors.affiliation: Institute for Immunology, University Medical Centre, Johannes Gutenberg University Mainz, D55131 Mainz, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Institute for Immunology, University Medical Centre, Johannes Gutenberg University Mainz, D55131 Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: 1] University of Orleans and CNRS UMR7355, Transgenose Institute, 45071 Orleans, France [2] Institute of Infectious Disease and Molecular Medicine (IIDMM), University of Cape Town, 7700 Rondebosch, RSA.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: 1] Department of Immunology, Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK [2] CEGMR, King Abdul-Aziz University, Jeddah 21589, Kingdom of Saudi Arabia [3] School of Biological &Basic Medical Science, Soochow University, Suzhou 215006, China.
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D004802:Eosinophilia / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D016906:Interleukin-9 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000737:chemistry*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007376:Interleukin-2; D016906:Interleukin-9; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D050799:STAT5 Transcription Factor; D016159:Tumor Suppressor Protein p53; D000099218:Interferon Regulatory Factor-4; C496319:NOS2 protein, human; C496317:Nos2 protein, mouse
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