Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies

• Published in: Immunology Vol. 128; no. 1pt2; pp. e589 - e599
• Main Authors: Kondo, Masahiro, Murakawa, Yohko, Harashima, Nanae, Kobayashi, Shotai, Yamaguchi, Shuhei, Harada, Mamoru
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.09.2009; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: agonists; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Caspase 3; Caspase 3 - drug effects; Caspase 3 - immunology; Caspase 8; Caspase 8 - drug effects; Caspase 8 - metabolism; CD4-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Line; Cells, Cultured; dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; drug effects; Fas; Fas Ligand Protein; Fas Ligand Protein - immunology; Fas Ligand Protein - metabolism; fas Receptor; fas Receptor - agonists; fas Receptor - metabolism; Humans; immunology; inflammatory myopathy; Interferon-gamma; Interferon-gamma - pharmacology; Interleukin-12 Subunit p35; Interleukin-12 Subunit p35 - metabolism; Interleukin-17; Interleukin-17 - metabolism; Interleukin-1beta; Interleukin-1beta - pharmacology; Interleukin-23; Interleukin-23 - immunology; Interleukin-23 - metabolism; Interleukin-23 Subunit p19; Interleukin-23 Subunit p19 - metabolism; metabolism; Muscle Cells; Muscle Cells - drug effects; Muscle Cells - immunology; Myositis; Myositis - immunology; Myositis - pathology; Original; pathology; pharmacology; T helper 17; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0019-2805; 1365-2567; 1365-2567
• DOI: 10.1111/j.1365-2567.2008.03039.x

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-γ, tumour necrosis factor-α, and interleukin (IL)-1β 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.