+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: not found

      Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells.

      The Journal of Immunology Author Choice

      physiology, Animals, Antibodies, Monoclonal, Apoptosis, immunology, Cell Line, Transformed, Cells, Cultured, Chemokines, biosynthesis, Glomerular Mesangium, metabolism, I-kappa B Proteins, Inflammation Mediators, Interferon-gamma, Interleukin-1, Interleukin-6, Mesangial Cells, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Phosphorylation, Receptors, Tumor Necrosis Factor, genetics, Tumor Necrosis Factor-alpha, Tumor Necrosis Factors, antagonists & inhibitors, Up-Regulation

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          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-1beta. CXCL11/interferon-inducible T cell alpha 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 Ikappa-B, while pretreatment with an Ikappa-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-kappaB 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.

          Related collections

          Author and article information



          Comment on this article