Participation of protein kinases in staurosporine-induced interleukin-6 production by rat peritoneal macrophages.
The incubation of rat peritoneal macrophages in the presence of staurosporine, a non-specific protein kinase inhibitor, induced interleukin-6 (IL-6) production in a time- and concentration-dependent manner at 6.3-63 nM, but at 210 nM, the stimulant effect on IL-6 production was reduced. The levels of IL-6 mRNA as determined by a reverse transcription-polymerase chain reaction were also increased by staurosporine in parallel with the ability to induce IL-6 production. Compounds structurally related to staurosporine including K-252a (non-specific protein kinase inhibitor) and KT-5720 (inhibitor of cyclic AMP-dependent protein kinase, PKA), did not increase IL-6 production by peritoneal macrophages. Staurosporine-induced increases in IL-6 production and expression of IL-6 mRNA were decreased by the PKC inhibitors, H-7 (2.7-27 microM), Ro 31-8425 (1-10 microM) and calphostin C (0.3-3 microM) and by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 (30-100 microM), but were further increased by the protein tyrosine kinase (PTK) inhibitor, genistein (12-37 microM). The staurosporine-induced increase in IL-6 production was not affected by the PKA inhibitor, H-89 (0.1-3 microM). These findings suggest that the induction of IL-6 production by staurosporine is secondary to elevation of IL-6 mRNA level, which, in turn, is positively regulated by the activation of PKC and PI 3-kinase and negatively regulated by the activation of PTK. PKA does not appear to play a significant role.
Yamaki
K
K
Department of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
Ohuchi
K
K
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000494:pharmacology*; D013449:Sulfonamides; D013997:Time Factors
D002227:Carbazoles; D002867:Chromones; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D007211:Indoles; D015850:Interleukin-6; D007546:Isoquinolines; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D013449:Sulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C057416:KT 5720; C049985:staurosporine aglycone; D019833:Genistein; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide