title: Inhibition of the TWEAK/Fn14 pathway attenuates autoimmune arthritis in a SKG mouse model.
abstract: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that is involved in pathogenesis of abnormal or disregulated inflammation. To verify how TWEAK/fibroblast growth factor-inducible gene 14 (Fn14) signals affect development of Th17 cells in arthritis, we utilized the SKG mouse, which spontaneously develops Th17-mediated autoimmune arthritis. Fn14-Fc was administered to zymosan A-induced arthritogenic SKG mice, and the effects in vivo were examined. Destruction of cartilage and bone damage was assessed by Hematoxylin and Eosin, and safranin O staining of the affected tissues. Phenotypic analysis of cells expressing inflammatory cytokines and angiogenesis-related factors, and the expression of transcription factor STAT3 in the affected joints were determined by immunohistochemistry. Blockade of Fn14 with Fn14-Fc reduced the clinical and histologic scores of inflammatory arthritis in the mouse model of spontaneously developed chronic autoimmune arthritis. Fn14-Fc suppressed production of inflammatory cytokines and angiogenesis-promoting factors, such as vascular endothelial growth factor and matrix metalloproteinase 3. Moreover, blocking of the TWEAK signal inhibited expression of STAT3 as well as interleukin-17 and -21 produced by Th17 cells. These results implicate TWEAK as a potential molecular target for treatment or prevention of inflammatory arthritis and autoimmune diseases such as rheumatoid arthritis.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jin-Sil
authors.initials: JS
authors.lastname: Park
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Min
authors.initials: SM
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: Kyung-Ah
authors.initials: KA
authors.lastname: Jung
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.|Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South 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, Seoul, South Korea.|Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea. iammila@catholic.ac.kr.
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, Seoul, South Korea.|Divison of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea. rapark@catholic.ac.kr.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology*; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000074050:TWEAK Receptor; D058504:Th17 Cells / Q000276:immunology*; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology*
chemical_list: D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors