title: IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Mayoko
authors.initials: M
authors.lastname: Asakawa
authors.forename: Miyuri
authors.initials: M
authors.lastname: Kawasumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D053583:Interleukin-1beta / Q000009:adverse effects / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007596:Joints / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology; D010880:Piperidines; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000276:immunology / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D015850:Interleukin-6; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D053245:RANK Ligand; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C479163:tofacitinib