title: IL-1 receptor antagonist (IL-1Ra)-Fc ameliorate autoimmune arthritis by regulation of the Th17 cells/Treg balance and arthrogenic cytokine activation.
abstract: IL-1β signalling has a critical role in the pathogenesis of various types of inflammatory arthritis including rheumatoid arthritis (RA). We aimed to investigate the therapeutic effects of human IL-1 receptor antagonist with Fc fragment (hIL-1Ra-Fc) on autoimmune arthritis and to identify the possible mechanisms by which hIL-1RA-Fc exerts anti-arthritic effects in a murine model of RA and patients with rheumatoid arthritis.
  
  
  
  Collagen-induced arthritis (CIA) murine model was established in DBA/1J mice. The levels of various cytokines were determined by using enzyme-linked immunosorbent assay. The mouse joints were assessed for clinical arthritis score and histologic features. Th17 cells and Treg cells were stained by using antibodies specific for CD4, IL-17, CD25, and FoxP3. Osteoclastogenesis was determined by TRAP staining and real-time PCR.
  
  
  
  hIL-1RA-Fc reduced the arthritis incidence, histological inflammation and cartilage score in the CIA model. The expression of proinflammatory cytokines, VEGF and RANK, was reduced in the affected joint of hIL-1Ra-Fc-treated mice. hIL-1Ra-Fc-treated mice showed decreased number of Th17 cells with increased number of Treg cells in spleens. hIL-1Ra-Fc reduced Th17 cell differentiation by inactivation of STAT3 signalling, and reciprocally induced Treg cell differentiation through STAT5 signalling. In addition, the expression of IL-17, TNF-α, RANKL, and VEGF was decreased, while Foxp3 gene expression was increased in PBMCs of RA patients after administration of hIL-1Ra-Fc.
  
  
  
  The anti-arthritis effects of hIL-1RA-Fc are associated with regulation of balance between Th17 cells and Treg cells and suppression of osteoclastogenesis and angiogenesis in the affected joints.
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea. Electronic address: seonyeong@catholic.ac.kr.
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea; Division of Rheumatology, Department of internal Medicine, School of Medicine, The Catholic University of Korea, Seoul 137-070, South Korea. Electronic address: alsghdrl1921@naver.com.
authors.forename: Hong Ki
authors.initials: HK
authors.lastname: Min
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea. Electronic address: redcap817@catholic.ac.kr.
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: HANDOK Inc. 132, Theheran street, Gangnam-gu, Seoul 135-755, South Korea. Electronic address: hyejeong.shin@handok.com.
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: HANDOK Inc. 132, Theheran street, Gangnam-gu, Seoul 135-755, South Korea. Electronic address: woonyoung.lee@handok.com.
authors.forename: Woon Young
authors.initials: WY
authors.lastname: Lee
authors.affiliation: HANDOK Inc. 132, Theheran street, Gangnam-gu, Seoul 135-755, South Korea. Electronic address: younggyu.cho@handok.com.
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Cho
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea; Division of Rheumatology, Department of internal Medicine, School of Medicine, The Catholic University of Korea, Seoul 137-070, South Korea. Electronic address: seungki73@catholic.ac.kr.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea; Division of Rheumatology, Department of internal Medicine, School of Medicine, The Catholic University of Korea, Seoul 137-070, South Korea. Electronic address: juji@catholic.ac.kr.
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea. Electronic address: iammila@catholic.ac.kr.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, South Korea; Division of Rheumatology, Department of internal Medicine, School of Medicine, The Catholic University of Korea, Seoul 137-070, South Korea. Electronic address: rapark@catholic.ac.kr.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007167:Immunotherapy / Q000379:methods*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D053590:Interleukin 1 Receptor Antagonist Protein; D011994:Recombinant Proteins
keywords: Angiogenesis; Autoimmune arthritis; IL-1 receptor antagonist; Osteoclastogenesis; Regulatory T cells; Th17 cells