title: Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells.
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-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.
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Campbell
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Gao
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
authors.forename: Lihe
authors.initials: L
authors.lastname: Su
authors.forename: Beth
authors.initials: B
authors.lastname: Browning
authors.forename: Timothy
authors.initials: T
authors.lastname: Zheng
authors.forename: Lena
authors.initials: L
authors.lastname: Schiffer
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000276:immunology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D000074049:Cytokine TWEAK; D005920:Glomerular Mesangium / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; D000074049:Cytokine TWEAK; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; C000606205:Nfkbia protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma