title: Digoxin ameliorates autoimmune arthritis via suppression of Th17 differentiation.
abstract: Digoxin is a cardiac glycoside that is commonly used to treat heart failure. Based on its known anti-inflammatory effect, this study was undertaken to investigate the effect of digoxin on collagen-induced arthritis (CIA) and to delineate the underlying mechanism. Digoxin or vehicle was injected intraperitoneally thrice weekly in mice with CIA, from day 7 or day 35 after immunization to investigate preventive or therapeutic effect, respectively. The incidence and severity of arthritis was evaluated. Digoxin treatment suppressed the incidence of arthritis and joint inflammation in mice with CIA. The expression of IL-17 and other proinflammatory cytokines, including IL-1β, IL-6, TNF-α and IL-21, were markedly reduced in the arthritic joints of digoxin-treated CIA mice. Th17 cells and CD4(+) pSTAT3(+) cells were less frequently observed in the spleen of digoxin-treated CIA mice than controls. The mRNA expression of IL-17 and ROR γt was consistently lower in total splenocytes or draining lymph node cells obtained from digoxin-treated CIA mice. Digoxin also reduced in vitro Th17 differentiation and LPS-stimulated IgG production. The number of osteoclasts in the arthritic joint was lower in digoxin-treated mice, whereas digoxin treatment did not directly suppress in vitro osteoclastogenesis. Our findings suggest that digoxin can regulate Th17 and reciprocally promote Treg cells and suppress joint inflammation and bone erosion in CIA. Digoxin may be a therapeutic option by targeting pathogenic Th17 and immunoglobulin production, for treatment of autoimmune arthritis and other Th17-related diseases.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of 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, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Seungye
authors.initials: S
authors.lastname: Baek
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Jaeseon
authors.initials: J
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Juhyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of 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, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea. Electronic address: seungki73@catholic.ac.kr.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004077:Digoxin / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008811:Mice, Inbred DBA; D058504:Th17 Cells / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D004077:Digoxin
keywords: Digoxin; IL-17 producing T cells; ROR γt; Regulatory T cells; Rheumatoid arthritis