The role of TWEAK/Fn14 interactions in antibody induced glomerulonephritis
TWEAK (TNFSF12) is a recently described cytokine belonging to the TNF ligand superfamily. In various cell types, TWEAK can promote either cell death or proliferation in addition to the release of proinflammatory mediators such as chemokines whose functions have been linked to lupus nephritis. Therefore, we characterized the expression and function of TWEAK and Fn14 in the kidney and studied its role in antibody-induced nephritis.;In both primary and SV-40 transformed C57Bl/6 MC and in a murine podocyte cell line we detected the presence of TWEAK mRNA. By flow cytometry, we found that mesangial cells (MC) derived from MRL-lpr, BALB/c, and C57Bl/6 mice in addition to a murine podocyte cell line express TWEAK receptors on the cell surface. Exposing MC to TWEAK caused NF-kappaB pathway activation, apoptosis (in combination with IFN-gamma) and induced a dose and time dependent increase in several proinflammatory mediators, including CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10 and CXCL1/KC. Chemokine secretion was abolished using soluble Fn14, Fn14 deletion, monoclonal anti-TWEAK antibodies and the NF-kappaB pathway inhibitor, BAY11-7082. What's more, we found that IL-1beta, IFN-alpha and IFN-gamma consistently induced TWEAK secretion in C57Bl/6 MC but not MRL-lpr tubular cells. Furthermore, an intravenous injection of Fc-TWEAK into C57Bl/6 mice induced an increase in kidney macrophages as compared to control treated mice.;Evaluating the role of TWEAK in antibody-mediated nephritis, we found an increase in kidney TWEAK mRNA expression in MRL-lpr and NZB/W F1 lupus-prone mouse strains compared to BALB/c non-autoimmune mice, which, using immunohistochemistry, localized to the glomeruli and tubules. Inducing nephrotoxic serum nephritis in 129/Sv mice, we found that Fn14-/- mice or anti-TWEAK antibody treatment demonstrated significantly decreased proteinuria compared to controls. Furthermore, Fn14-/- mice displayed a significantly decreased anti-rabbit IgG response and chemokine mRNA levels compared to Fn14 +/+ mice.;In conclusion, TWEAK signaling via Fn14 on resident kidney cells induces multiple pro-inflammatory chemokines, which are pivotal mediators in the pathogenesis of immune complex glomerulonephritis and lupus-like nephropathy. Furthermore, inhibition of TWEAK/Fn14 interactions may be an innovative approach for the treatment of inflammatory renal diseases.
Source: Dissertation Abstracts International, Volume: 69-12, Section: B, page: 7399.;Advisors: Chaim Putterman.