The roles of protein kinase C and cyclic nucleotide dependent kinase in signal transduction in human interferon gamma induction by poly I:poly C.
The signal transduction mechanisms involved in interferon (IFN) gamma induction in human peripheral mononuclear lymphocyte nylon-nonadherent cells (NNA cells) by stimulation with poly(I):poly(C) are investigated. Significant enhancement of IFN gamma production by poly(I):poly(C) is observed in the presence of the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA, a protein kinase C (PKC) activator). Our study shows that in NNA cells, poly(I):poly(C) with or without TPA causes prolonged activation of cytosolic PKC of NNA cells for at least 120 min. The level of activation of PKC is quite remarkable in the case of the combined stimulation by poly(I):poly(C) and TPA as compared to poly(I):poly(C) alone. This demonstrates that prolonged activation of cytosolic PKC for at least 120 min is essential for high levels of production of IFN gamma. Moreover, inhibition experiments using the PKC inhibitor H-7 and cAMP-dependent protein kinase inhibitor H-8 suggest that the mechanism of signal transduction with regard to PKC is involved in stimulation of IFN gamma production in NNA cells by poly(I):poly(C) in the presence of TPA and that along with PKC, cAMP-dependent protein kinase is probably involved in induction of IFN gamma by stimulation with poly(I):poly(C) alone.
Tamura-Nishimura
M
M
Japanese Red Cross, Central Blood Center, Tokyo.
Sasakawa
S
S
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007546:Isoquinolines / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D007546:Isoquinolines; D010703:Phorbol Esters; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D007371:Interferon-gamma; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D011070:Poly I-C