title: Treatment of IL-21R-Fc control autoimmune arthritis via suppression of STAT3 signal pathway mediated regulation of the Th17/Treg balance and plasma B cells.
abstract: Interleukin-21 (IL-21) is a T cell-derived cytokine modulating T cell, B cell, and natural killer cell responses. To determine whether IL-21 contributes to pathologic processes, recombinant IL-21 receptor (R) fusion protein (rhIL-21R-Fc) was examined in mice models of autoimmune arthritis (collagen-induced arthritis). DBA/1J mice were immunized with chicken type II collagen and then treated intraperitoneally with rhIL-21R-Fc, which was initiated after the onset of arthritis symptoms in 20% of the cohort. The mice were assessed 3 times per week for signs of arthritis and histologic features as well as serum immunoglobulin. Cytokine messenger RNA levels in the spleen were also examined. STAT3 phosphorylation is dose dependently activated by IL-21 and inhibited by rhIL-21R-Fc in vitro using T cells. Treatment of DBA/1J mice with rhIL-21R-Fc reduced the clinical and histologic signs of CIA. The IL-17 and STAT3-expressing CD4(+) splenocytes dramatically decreased in the rhIL-21R-Fc treated mice. IL-21R-Fc treated mice also decreased the production of IgG, STAT3 phosphorylation, and plasma cell transcription factor (Blimp1). These findings demonstrate a pathogenic role of IL-21 in animal models of RA, suggesting IL-21 as a promising therapeutic target among human RA.
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Jun-Geol
authors.initials: JG
authors.lastname: Ryu
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Hyeon-Beom
authors.initials: HB
authors.lastname: Seo
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Jin-Sil
authors.initials: JS
authors.lastname: Park
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Moon
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Yuseong-gu, Daejeon 618-806, South Korea.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Yoo
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Yuseong-gu, Daejeon 618-806, South Korea.
authors.forename: Young-woo
authors.initials: YW
authors.lastname: Park
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: Rheumatism Research Center, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040, South Korea. Electronic address: iammila@catholic.ac.kr.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University, Neungdong-ro, Seoul 143-701, South Korea. Electronic address: ho0172@kuh.ac.kr.
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D008811:Mice, Inbred DBA; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D007074:Immunoglobulin G; D020381:Interleukin-17; D007378:Interleukins; C513258:Prdm1 protein, mouse; D053655:Receptors, Interleukin-21; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098546:Interleukin-21
keywords: Autoimmune arthritis; IL-21R-Fc; Plasma cell; STAT3; Th17