title: TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes.
abstract: X-box binding protein 1 (XBP1) is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes. XBP1 can also be activated in direct response to Toll-like receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Here we show that TLR-dependent XBP1 activation is operative in the synovial fibroblasts (SF) of patients with active rheumatoid arthritis (RA). We investigated the expression of ER stress response genes in patients with active RA and also in patients in remission. The active (spliced) form of (s)XBP1 was significantly overexpressed in the active RA group compared to healthy controls and patients in remission. Paradoxically, expression of nine other ER stress response genes was reduced in active RA compared to patients in remission, suggestive of a UPR-independent process. However, sXBP1 was induced in SF by TLR4 and TLR2 stimulation, resulting in sXBP1-dependent interleukin-6 and tumour necrosis factor (TNF) production. We also show that TNF itself induces sXBP1 in SF, thus generating a potential feedback loop for sustained SF activation. These data confirm the first link between TLR-dependent XBP1 activation and human inflammatory disease. sXBP1 appears to play a central role in this process by providing a convergence point for two different stimuli to maintain activation of SF.
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Savic
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Lylia
authors.initials: L
authors.lastname: Ouboussad
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Dickie
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Janina
authors.initials: J
authors.lastname: Geiler
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Chi
authors.initials: C
authors.lastname: Wong
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Doody
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Churchman
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Frederique
authors.initials: F
authors.lastname: Ponchel
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK; NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Cook
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Maya H
authors.initials: MH
authors.lastname: Buch
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Reuben M
authors.initials: RM
authors.lastname: Tooze
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner Building, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. Electronic address: M.McDermott@leeds.ac.uk.
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019898:Autocrine Communication; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D061251:Primary Cell Culture; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071701:Regulatory Factor X Transcription Factors; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C439524:TNF protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human
keywords: Rheumatoid arthritis (RA); Toll-like receptor (TLR); Unfolded protein response (UPR); sXBP1