Protein synthesis-dependent potentiation by thyroxine of antiviral activity of interferon-gamma.
We have studied the prenuclear signal transduction pathway by which thyroid hormone potentiates the antiviral activity of human interferon-gamma (IFN-gamma) in HeLa cells, which are deficient in thyroid hormone receptor (TR). The action of thyroid hormone was compared with that of milrinone, which has structural homologies with thyroid hormone. L-Thyroxine (T4), 3,5,3'-L-triiodothyronine (T3), and milrinone enhanced the antiviral activity of IFN-gamma up to 100-fold, a potentiation blocked by cycloheximide. The 5'-deiodinase inhibitor 6-n-propyl-2-thiouracil did not block the T4 effect. 3,3',5,5'-Tetraiodothyroacetic acid prevented the effect of T4 but not of milrinone. The effects of T4 and milrinone were blocked by inhibitors of protein kinases C (PKC) and A (PKA) and restored by PKC and PKA agonists; only the effect of T4 was blocked by genistein, a tyrosine kinase inhibitor. In separate models, milrinone was shown not to interact with nuclear TR-beta. T4 potentiation of the antiviral activity of IFN-gamma requires PKC, PKA, and tyrosine kinase activities but not traditional TR.
Lin
H Y
HY
Department of Medicine, Albany Medical College and Stratton Veterans Affairs Medical Center, New York 12208, USA.
Yen
P M
PM
Davis
F B
FB
Davis
P J
PJ
D000676:Amrinone / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D007700:Kinetics; D020105:Milrinone; D008954:Models, Biological; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011441:Propylthiouracil / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000494:pharmacology; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013974:Thyroxine / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D011500:Protein Synthesis Inhibitors; D011728:Pyridones; D011994:Recombinant Proteins; D014284:Triiodothyronine; D011441:Propylthiouracil; D007371:Interferon-gamma; D003513:Cycloheximide; D019833:Genistein; D007453:Iodide Peroxidase; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020105:Milrinone; D000676:Amrinone; D013974:Thyroxine