title: Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators.
abstract: Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1β. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hung N
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Erika H
authors.initials: EH
authors.lastname: Noss
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Mizoguchi
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Huppertz
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Wei
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gerald F M
authors.initials: GFM
authors.lastname: Watts
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: mbrenner@research.bwh.harvard.edu.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology; D019898:Autocrine Communication / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D053605:Leukemia Inhibitory Factor / Q000276:immunology*; D053606:Receptors, OSM-LIF / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D059467:Transcriptome
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D053606:Receptors, OSM-LIF; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human
keywords: IL-33; IL-6; IL-8; LIF; LIFR; STAT4; fibroblasts; interleukin-33; interleukin-6; interleukin-8; leukemia inhibitor factor; leukemia inhibitor factor receptor; rheumatoid arthritis; signal transducer and activator of transcription 4; stromal cells; synovium