title: Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis.
abstract: Cytokine control of the synovial infiltrate is a central process in the development of inflammatory arthritis. In this study, we combine genetic approaches and intervention strategies to describe a fundamental requirement for IL-6-mediated STAT3 signaling in orchestrating the inflammatory infiltrate in monoarticular and systemic models of experimental arthritis. STAT3 activation via the common gp130 signal-transducing receptor for all IL-6-related cytokines led to increased retention of neutrophils and T cells within the inflamed synovium, which included STAT3-regulated IL-17A-secreting T cells. Control of leukocyte infiltration was reliant upon IL-6 signaling via its soluble receptor (termed IL-6 trans signaling), as evidenced by selective blockade of this alternative IL-6 signaling pathway using an engineered variant of soluble gp130 (sgp130Fc). This therapeutic intervention led to substantial clinical improvement in mice with emerging or established incidence of systemic arthritis. These data illustrate that IL-6 control of STAT3 is critical for regulating the synovial infiltrate in inflammatory arthritis, and suggest that selective inhibition of IL-6 trans signaling may provide a more refined intervention strategy for blocking IL-6-driven proarthritic activities.
authors.affiliation: Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom.
authors.forename: Mari A
authors.initials: MA
authors.lastname: Nowell
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Carty
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hayes
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Richards
authors.forename: Simon
authors.initials: S
authors.lastname: Slinn
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012008:Recurrence; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C494200:Il6st protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; C519852:olamkicept