INTERLEUKIN 1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCE A MACROPHAGE-TYPE OF NITRIC-OXIDE SYNTHASE IN RAT RENAL MESANGIAL CELLS

Treatment of mesangial cells with interleukin 1-beta (IL-1-beta) or tumour necrosis factor alpha (TNF-alpha) has been shown to increase cGMP formation, most probably due to induction of nitric oxide synthase. Here we report that maximum stimulation of cGMP formation over a 24-h period required the presence of IL-1-beta or TNF-alpha during the first 18 h of induction. N4-monomethyl-L-arginine (L-NMMA) was a potent inhibitor of cytokine-induced cGMP formation while N4-nitro-L-arginine (L-NNA) was less active. Formation of nitric oxide was detected in the cytosol of cytokine-treated mesangial cells by activation of purified soluble guanylate cyclase and was stimulated by tetrahydrobiopterin, but not by calcium calmodulin. Treatment of cells with IL-1-beta or TNF-alpha markedly attenuated the contractile response to a subsequent challenge with angiotensin II. Furthermore, conditioned medium from IL-1-beta-treated cells increased cGMP in untreated control cells.