Cyclosporin derivatives inhibit interleukin 1 beta induction of nitric oxide synthase in renal mesangial cells.
Treatment of mesangial cells with recombinant human interleukin 1 beta 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 beta-induced nitrite generation. Half-maximal inhibition was observed at concentrations of 0.9 microM, 2.0 microM and 3.8 microM 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 1 beta stimulus and still caused maximal inhibition of nitrite production. Furthermore, interleukin 1 beta 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 1 beta-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.
Mühl
H
H
Department of Pharmacology, Biocenter, University of Basel, Switzerland.
Kunz
D
D
Rob
P
P
Pfeilschifter
J
J
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D003524:Cyclosporins; D007375:Interleukin-1; D009573:Nitrites; D012333:RNA, Messenger; D011994:Recombinant Proteins; C045571:cyclosporin G; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C050025:cyclosporin H; D016559:Tacrolimus