Proinflammatory effects of Tweak/Fn14 interactions in glomerular mesangial cells

Sean Campbell, Linda C. Burkly, Hua Xin Gao, Joan W. Berman, Lihe Su, Beth Browning, Timothy Zheng, Lena Schiffer, Jennifer S. Michaelson, Chaim Putterman

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

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-γ-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-α + IL-1β. CXCL11/interferon-inducible T cell α 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 Iκ-B, while pretreatment with an Iκ-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-κB 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.

Original languageEnglish (US)
Pages (from-to)1889-1898
Number of pages10
JournalJournal of Immunology
Volume176
Issue number3
DOIs
StatePublished - Feb 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Campbell, S., Burkly, L. C., Gao, H. X., Berman, J. W., Su, L., Browning, B., Zheng, T., Schiffer, L., Michaelson, J. S., & Putterman, C. (2006). Proinflammatory effects of Tweak/Fn14 interactions in glomerular mesangial cells. Journal of Immunology, 176(3), 1889-1898. https://doi.org/10.4049/jimmunol.176.3.1889