Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amrinone / pharmacology
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Antiviral Agents / pharmacology*
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cycloheximide / pharmacology*
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Genistein / pharmacology
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HeLa Cells
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Humans
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Interferon-gamma / pharmacology*
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Iodide Peroxidase / antagonists & inhibitors
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Kinetics
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Milrinone
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Models, Biological
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Phosphodiesterase Inhibitors / pharmacology
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Propylthiouracil / pharmacology
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Synthesis Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Pyridones / pharmacology
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Recombinant Proteins
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Thyroxine / pharmacology*
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Triiodothyronine / pharmacology
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Vesicular stomatitis Indiana virus / drug effects
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Vesicular stomatitis Indiana virus / physiology*
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Virus Replication / drug effects*
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Phosphodiesterase Inhibitors
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Protein Synthesis Inhibitors
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Pyridones
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Recombinant Proteins
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Triiodothyronine
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Propylthiouracil
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Interferon-gamma
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Cycloheximide
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Genistein
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Iodide Peroxidase
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Protein-Tyrosine Kinases
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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Milrinone
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Amrinone
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Thyroxine