Seon-Yeong Lee1, Hong Ki Min2, Seung Hoon Lee3, Hye Jeong Shin4, Woon Young Lee5, Young-Gyu Cho6, Seung-Ki Kwok7, Ji Hyeon Ju8, Mi-La Cho9, Sung-Hwan Park10. 1. 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. 2. 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. 3. 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. 4. HANDOK Inc. 132, Theheran street, Gangnam-gu, Seoul 135-755, South Korea. Electronic address: hyejeong.shin@handok.com. 5. HANDOK Inc. 132, Theheran street, Gangnam-gu, Seoul 135-755, South Korea. Electronic address: woonyoung.lee@handok.com. 6. HANDOK Inc. 132, Theheran street, Gangnam-gu, Seoul 135-755, South Korea. Electronic address: younggyu.cho@handok.com. 7. 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. 8. 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. 9. 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. 10. 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.
Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
INTRODUCTION: 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 humanIL-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. METHODS: 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. RESULTS: 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 RApatients after administration of hIL-1Ra-Fc. CONCLUSION: 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: Maha M Eissa; Dalia K Mostafa; Amany A Ghazy; Mervat Z El Azzouni; Laila M Boulos; Layla K Younis Journal: PLoS One Date: 2016-11-01 Impact factor: 3.240