title: HtrA2 suppresses autoimmune arthritis and regulates activation of STAT3.
abstract: Rheumatoid arthritis (RA) is an autoimmune disease that is related to the induction of T helper (Th)17 cells, which secrete interleukin-17, and activation of the signal transducer and activator of transcription (STAT) 3. The expression of high-temperature requirement protein A (HtrA) 2, a serine protease involved in apoptosis, was decreased in RA patients nonresponsive to drug treatment of RA. The aim of this study was to determine whether overexpression of HtrA2 has a therapeutic effect on RA. Th17 differentiation, osteoclastogenesis, and lymphocyte activation are increased in motor neuron degeneration (mnd)2 mice, which lack HtrA2 activity because of a missense mutation (Ser276Cys) in the protease domain of HtrA2. The inhibitor of HtrA2 also increased Th17 differentiation. On the other hand, HtrA2 induced cleavage of STAT3 and overexpression of HtrA2 attenuated CIA in a mouse model. HtrA2 overexpression inhibited plaque development as well as the differentiation of Th17 in ApoE-/-mice after immunization with proteoglycans to induce a hyperlipidemia-based RA animal model. The therapeutic function of HtrA2 in inflammatory diseases is linked with Th17 development and the STAT3 pathway in splenocytes. These results suggest that HtrA2 participates in immunomodulatory activity where the upregulation of HtrA2 may shed light on therapeutic approaches to RA and hyperlipidemia.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Seung Hoon
authors.initials: SH
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, Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Moon
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Hyeon-Beom
authors.initials: HB
authors.lastname: Seo
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.|Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Junyeong
authors.initials: J
authors.lastname: Yi
authors.affiliation: Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.|Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Nam
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jun-Ki
authors.initials: JK
authors.lastname: Min
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.|Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Hyangshuk
authors.initials: H
authors.lastname: Rhim
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Laboratory of Immune Network, Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001327:Autoimmune Diseases; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D000074923:High-Temperature Requirement A Serine Peptidase 2 / Q000235:genetics*; D006949:Hyperlipidemias / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D058504:Th17 Cells / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D011509:Proteoglycans; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse