Potentiation by thyroxine of interferon-gamma-induced antiviral state requires PKA and PKC activities.
Added to HeLa cells previously exposed to recombinant human interferon (IFN)-gamma for 20 h, thyroid hormone [L-thyroxine (T4)] in physiological concentrations potentiates the antiviral action of IFN-gamma by more than 100-fold in 4 h. We examined protein kinase activities for their contributions to the mechanism of this posttranslational effect of thyroid hormone. Added concurrently with thyroid hormone, the protein kinase C (PKC) inhibitor CGP-41251 (5 nM) blocked T4 potentiation of IFN-gamma action. Coincubated with CGP-41251, phorbol 12-myristate 13-acetate (PMA) reversed the effect of the inhibitor on thyroid hormone action. U-73122 (10 nM), a phospholipase C inhibitor, also blocked hormone potentiation. KT-5720 (500 nM), a protein kinase A (PKA) inhibitor, completely inhibited the T4 effect, whereas 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) restored hormone action in the presence of KT-5720. In the absence of T4, 8-BrcAMP and PMA, added together to cells in the 4-h paradigm, fully reproduced hormone potentiation of the antiviral effect of IFN-gamma. Incubated individually with IFN-gamma-treated cells, the two agonists had no potentiating action. Thyroid hormone apparently must activate both PKA and PKC in the nongenomic pathway of IFN-gamma action to enhance antiviral activity in HeLa cells.
Department of Medicine, Albany Medical College, New York, USA.
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Lin
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Thacorf
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Davis
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Davis
D000818:Animals; D002147:Calmodulin / Q000494:pharmacology; D002227:Carbazoles; D000242:Cyclic AMP / Q000502:physiology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000008:administration & dosage*; D007739:L Cells; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D018353:Rhabdoviridae Infections / Q000503:physiopathology*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013974:Thyroxine / Q000008:administration & dosage*; D013997:Time Factors; D014721:Vesicular stomatitis Indiana virus; D014762:Viral Interference / Q000187:drug effects*
D002147:Calmodulin; D002227:Carbazoles; D004791:Enzyme Inhibitors; D004963:Estrenes; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; D013449:Sulfonamides; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C057416:KT 5720; C017967:W 7; D007371:Interferon-gamma; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin; D013755:Tetradecanoylphorbol Acetate; D013974:Thyroxine