title: IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy.
abstract: Fibroblast-like synoviocytes (FLSs) are a major cell population of the pannus that invades cartilage and bone in rheumatoid arthritis (RA). FLS resistance to apoptosis is a major characteristic of RA. The aims of this study were to investigate the effects of interleukin-17 (IL-17) and IL-17-producing T helper (Th17) cells on resistance to apoptosis in FLSs from RA patients (RA FLSs) and their roles in mitochondrial dysfunction and autophagy. Mitochondrial function was assessed in RA FLSs and FLSs from osteoarthritis patients (OA FLSs). FLSs were treated with IL-17 and their morphological features, respiratory level and mitochondrial gene expression were measured. The effects of IL-17 and Th17 cells on the relationship between autophagy and apoptosis were evaluated by measuring the expression of apoptosis-related genes using sodium nitroprusside or 3-methyladenine. The mitochondria of FLSs isolated from RA and osteoarthritis patients displayed different morphological and physiological features. RA FLSs exhibited greater autophagosome formation and greater dysfunction of mitochondrial respiration compared with OA FLSs. IL-17 induced mitochondrial dysfunction and autophagosome formation in RA FLSs, suggesting that they were resistant to apoptosis. Autophagy-related antiapoptosis induced by IL-17 was restored by inhibition of autophagy, suggesting a relationship between mitochondrial dysfunction and cell survival in RA FLSs. Th17 cells and IL-17 increased autophagy of RA FLSs by causing mitochondrial dysfunction. Our findings suggest that, in RA, interactions between RA FLSs and Th17 cells may be involved in the tumorous growth of FLSs and the formation of pannus in joints.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Kwon
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
authors.forename: Da Som
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Moon
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seocho-gu, Seoul, South Korea.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000235:genetics* / Q000276:immunology; D002356:Cartilage / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D007596:Joints / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D000070918:Synoviocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D020381:Interleukin-17