CYCLOSPORINE DERIVATIVES INHIBIT INTERLEUKIN-1-BETA INDUCTION OF NITRIC-OXIDE SYNTHASE IN RENAL MESANGIAL CELLS

Treatment of mesangial cells with recombinant human interleukin 1beta dose dependently increased nitrite formation due to the induction of a macrophage-type of nitric oxide (NO) synthase. Addition of cyclosporin A, cyclosporin G or cyclosporin H dose dependently inhibited interleukin 1,6-induced nitrite generation. Half-maximal inhibition was observed at concentrations of 0.9 muM, 2.0 muM and 3.8 muM of cyclosporin A, cyclosporin G and cyclosporin H, respectively. Time-course studies indicated that cyclosporin A could be added up to 6 h after the interleukin 1beta stimulus and still caused maximal inhibition of nitrite production. Furthermore, interleukin 1beta increased NO synthase mRNA levels in mesangial cells and this effect was potently suppressed by all three cyclosporin derivatives. As cyclosporin H has no immunosuppressive activity, these data indicate that the inhibitory effect of the cyclosporin derivatives on NO synthase expression is not related to the immunosuppressive action of the drugs. This suggestion is further substantiated by the observation that the potent immunosuppressants rapamycin and FK506 did not alter interleukin 1beta-induced NO synthase mRNA levels or nitrite generation in mesangial cells. In summary, these data demonstrate that cyclosporin derivatives potently modulate the L-arginine-NO pathway in renal mesangial cells.