Enhancing effect of staurosporine on NO production in rat peritoneal macrophages via a protein kinase C-independent mechanism.
Staurosporine (3-100 nM), frequently used as a protein kinase C (PKC) inhibitor, increased accumulation of nitrite in the culture medium of rat peritoneal macrophages up to 6 times above the control level. Moreover, when used in combination with the stable analogue of cyclic AMP, dibutyrylcyclic AMP (db cyclic AMP; 0.1 mM), and/or a cytokine, tumour necrosis factor-alpha (TNF alpha; 100 u ml-1), staurosporine synergistically potentiated, up to 30 times, nitrite accumulation. On the other hand, the other PKC inhibitors, calphostin C and H-7 (10 nM-10 microM) were not effective under the same conditions. The staurosporine-induced nitrite accumulation, in both the presence and the absence of TNF alpha and/or db cyclic AMP was effectively inhibited by the protein synthesis inhibitor, cycloheximide, or by the nitric oxide (NO) synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA). Thus our data suggest that staurosporine may enhance NO production in macrophages via intracellular mechanisms unrelated to the PKC inhibition.
Neuropeptide Research Department, Polish Academy of Sciences, Kraków, Poland.
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Sowa
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Przewłocki
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects*; D051381:Rats; D019311:Staurosporine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000470:Alkaloids; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000242:Cyclic AMP; D011493:Protein Kinase C; D019311:Staurosporine