NITRIC-OXIDE SYNTHESIS IN RAT MESANGIAL CELLS INDUCED BY CYTOKINES

The production of nitric oxide (NO) is increased in experimental nephr itis, with NO thought to be an important mediator of cell damage. The cytokines interleukin 1 beta (IL-1 beta), IL-6, IL-8, monocyte chemota ctic protein-1 (MCP-1) and transforming growth factor-beta (TGF-beta) are released from mesangial cells in vitro or are expressed in various forms of glomerulonephritis. We investigated the effects of these cyt okines on NO synthesis in cultured rat mesangial cells. Incubation of mesangial cells with IL-1 beta (10 ng/ml) for 24 h increased the accum ulation of NO and guanosine 3',5'-cyclic monophosphate (cGMP). IL-6, I L-8, MCP-1 and TGF-beta showed no significant effect on the production of NO or cGMP. Transcripts of the inducible NO synthase (iNOS) gene w ere not detected in unstimulated mesangial cells. However, exposure of cells to IL-1 beta (10 ng/ml) for 24 h resulted in the appearance of iNos mRNA. IL-1 beta-induced NO synthesis was significantly inhibited by N-G-monomethyl-L-arginine, cycloheximide, actinomycin D, dexamethas one, and TGF-beta. These results indicate that, of the various cytokin es studied, only IL-1 beta stimulates iNOS mRNA accumulation and NO sy nthesis in mesangial cells. NO may function in an autocrine manner to modulate the glomerular response to inflammation.