Protein kinase C-independent selective induction of nitric oxide synthase activity in rat alveolar macrophages by staurosporine.
The purpose of this study was to characterize the effect of the K-252a family of protein kinase inhibitors with emphasis on staurosporine (ST), on stimulation of the inducible nitric oxide synthase activity in rat alveolar NR8383 macrophages. We found that ST, but not K-252a, K-252b, KT-5720, and KT-5823, selectively enhanced the basal or the lipopolysaccharide (LPS)-induced nitric oxide production. ST-induced NO production was blocked by L-NAME, K-252a, and phosphatase inhibitors and could not be mimicked by other protein kinase C (PKC) inhibitors such as calphostine. An additive effect between ST and PMA on NO production was observed. LPS and PMA but not ST induced PKCbeta translocation from the cytosol to the membrane fraction. ST may induce and affect the state of phosphorylation of iNOS via PKC-independent mechanisms. ST provides an important pharmacological tool to investigate PKC-independent signal transduction pathways which regulate iNOS, induction, and activity in rat NR8383 macrophages.
Tabakman
R
R
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Lazarovici
P
P
Matsuda
Y
Y
Brodie
C
C
Ovadia
H
H
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D026121:Indole Alkaloids; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009573:Nitrites; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C049985:staurosporine aglycone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D010744:Phosphoric Monoester Hydrolases; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D019331:NG-Nitroarginine Methyl Ester