Protein kinase C inhibitors block the activation of macrophages by IFN-beta but not by IFN-gamma.
We investigated the role of protein kinase C (PK-C) in the activation of cytotoxic peritoneal murine macrophages (M phi) by IFN-gamma or by IFN-beta. Two potent inhibitors of PK-C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and retinal, were used. We found that both drugs inhibited in a dose-dependent manner the activation of cytotoxicity induced by IFN-beta, suggesting the requirement for intact PK-C activity in this process. In contrast, neither H-7 nor retinal inhibited the activation of cytotoxic M phi by IFN-gamma, indicating that IFN-gamma acts through a PK-C-independent pathway. The effectiveness of both drugs in inhibiting PK-C in intact M phi was evaluated by measuring the inhibition of induction of c-fos mRNA by L-alpha-1-oleoyl-2-acetoyl-sn-3-glycerol, a process that has been shown to be dependent on PK-C activation. We have found a strict correlation in the dose-dependent inhibition by both drugs of c-fos mRNA induction and activation of M phi by IFN-beta. These results indicate that different pathways of activation are triggered by IFN-gamma and IFN-beta, the former being independent from and the latter dependent on intact PK-C activity.
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004075:Diglycerides / Q000494:pharmacology; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos; D012172:Retinaldehyde / Q000494:pharmacology*; D012176:Retinoids / Q000494:pharmacology*
D004075:Diglycerides; D007370:Interferon Type I; D007546:Isoquinolines; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012176:Retinoids; D007371:Interferon-gamma; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D012172:Retinaldehyde