Proinflammatory effects of Tweak/Fn14 interactions in glomerular mesangial cells

被引:147
作者
Campbell, S
Burkly, LC
Gao, HX
Berman, JW
Su, LH
Browning, B
Zheng, T
Schiffer, L
Michaelson, JS
Putterman, C
机构
[1] Albert Einstein Coll Med, Div Rheumatol, Dept Microbiol & Immunol, Bronx, NY 10461 USA
[2] Biogen Idec Inc, Dept Exploratory Sci, Cambridge, MA USA
[3] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
[4] Hannover Med Sch, Div Nephrol, D-3000 Hannover, Germany
[5] Albert Einstein Coll Med, Div Rheumatol, Irving & Ruth Claremon Res Lab, Bronx, NY 10461 USA
关键词
D O I
10.4049/jimmunol.176.3.1889
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
TNF-like weak inducer of apoptosis, or TWEAK, is a relatively new member of the TNF-ligand superfamily. Ligation of the TWEAK receptor Fn14 by TWEAK has proinflammatory effects on fibroblasts, synoviocytes, and endothelial cells. Several of the TWEAK-inducible cytokines are important in the pathogenesis of kidney diseases; however, whether TWEAK can induce a proinflammatory effect on kidney cells is not known. We found that murine mesangial cells express cell surface TWEAK receptor. TWEAK stimulation of mesangial cells led to a dose-dependent increase in CCL2/MCP-1, CCL5/RANTES, CXCL10/IFN-gamma-induced protein 10 kDa, and CXCL1/KC. The induced levels of chemokines were comparable to those found following mesangial cell exposure to potent proinflammatory stimuli such as TNF-alpha + IL-1 beta. CXCL11/interferon-inducible T cell a chemoattractant, CXCR5, mucosal addressin cell adhesion molecule-1, and VCAM-1 were up-regulated by TWEAK as well. TWEAK stimulation of mesangial cells resulted in an increase in phosphorylated I kappa-B, while pretreatment with an I kappa-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-kappa B signaling pathway in TWEAK-induced chemokine secretion. Importantly, the Fn14-mediated proinflammatory effects of TWEAK on kidney cells were confirmed using mesangial cells derived from Fn14-deficient mice and by injection in vivo of TWEAK into wild-type vs Fn14-deficient mice. Finally, TWEAK-induced chemokine secretion was prevented by treatment with novel murine anti-TWEAK Abs. We conclude that TWEAK induces mesangial cells to secrete proinflammatory chemokines, suggesting a prominent role for TWEAK in the pathogenesis of renal injury. Our results support Ab inhibition of TWEAK as a potential new approach for the treatment of chemokine-dependent inflammatory kidney diseases.
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收藏
页码:1889 / 1898
页数:10
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