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|Title:||TWEAK is a novel arthritogenic mediator|
|Citation:||Journal of Immunology, 2006; 177(4):2610-2620|
|Publisher:||Amer Assoc Immunologists|
|Stuart J. Perper, Beth Browning, Linda C. Burkly, Shawn Weng, Cindy Gao, Keith Giza, Lihe Su, Leticia Tarilonte, Thomas Crowell, Luis Rajman, Laura Runkel, Martin Scott, Gerald J. Atkins, David M. Findlay, Timothy S. Zheng, and Henry Hess|
|Abstract:||TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1 (CCL-4), lymphotactin (XCL-1), IFN--inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.|
|Keywords:||Cells, Cultured; Animals; Mice, Inbred C57BL; Mice, Inbred DBA; Humans; Mice; Arthritis, Experimental; Collagen Type II; Tumor Necrosis Factors; Receptors, Tumor Necrosis Factor; Inflammation Mediators; Freund's Adjuvant; Ligands; Apoptosis; Male; Cytokine TWEAK; TWEAK Receptor|
|Description:||Copyright © 2006 by The American Association of Immunologists|
|Appears in Collections:||Orthopaedics and Trauma publications|
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