title: Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies.
abstract: Within the lesions of inflammatory myopathies, muscle fibres and invading mononuclear cells express Fas and Fas ligand (FasL), respectively. However, the roles of the Fas/FasL interaction in the pathogenesis of inflammatory myopathies are not fully understood. In the present study, we investigated the roles of proinflammatory cytokines and the Fas/FasL system in the pathogenesis of inflammatory myopathies. In vitro culturing of muscle cells with the proinflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, and interleukin (IL)-1beta synergistically increased Fas expression, susceptibility to Fas-mediated apoptosis, and the expression of cytoplasmic caspases 8 and 3. In addition, culturing of muscle cells with activated CD4(+) T cells induced muscle cell apoptosis, which was partially inhibited by anti-FasL antibody. We also tested the possibility that T helper (Th) 17, which is an IL-17-producing helper T-cell subset that plays crucial roles in autoimmune and inflammatory responses, participates in the pathogenesis of inflammatory myopathies. Interestingly, in vitro culturing of dendritic cells with anti-Fas immunoglobulin M (IgM) or activated CD4(+) T cells induced the expression of mRNA for IL-23p19, but not for IL-12p35, in addition to proinflammatory cytokines. Furthermore, IL-23p19 and IL-17 mRNAs were detected in the majority of biopsy samples from patients with inflammatory myopathies. Taken together, these results suggest that proinflammatory cytokines enhance Fas-mediated apoptosis of muscle cells, and that the Fas/FasL interaction between invading dendritic cells and CD4(+) T cells induces local production of IL-23 and proinflammatory cytokines, which can promote the proliferation of Th17 cells and enhance Fas-mediated apoptosis of muscle cells, respectively.
authors.affiliation: Department of Rheumatology, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kondo
authors.forename: Yohko
authors.initials: Y
authors.lastname: Murakawa
authors.forename: Nanae
authors.initials: N
authors.lastname: Harashima
authors.forename: Shotai
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D053148:Caspase 3 / Q000187:drug effects / Q000276:immunology; D053181:Caspase 8 / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D053222:Fas Ligand Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053765:Interleukin-12 Subunit p35 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects / Q000276:immunology*; D009220:Myositis / Q000276:immunology* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000819:agonists / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D053148:Caspase 3; D053181:Caspase 8