PROTEIN SYNTHESIS-DEPENDENT POTENTIATION BY THYROXINE OF ANTIVIRAL ACTIVITY OF INTERFERON-GAMMA

We have studied the prenuclear signal transduction pathway by which th yroid hormone potentiates the antiviral activity of human interferon-g amma (IFN-gamma) in HeLa cells, which are deficient in thyroid hormone receptor (TR). The action of thyroid hormone was compared with that o f milrinone, which has structural homologies with thyroid hormone. L-T hyroxine (T-4), 3,5,3'-L-triiodothyronine (T-3), and milrinone enhance d the antiviral activity of IFN-gamma up to 100-fold, a potentiation b locked by cycloheximide. The 5'-deiodinase inhibitor 6-n-propyl-2-thio uracil did not block the T-4 effect. 3,3',5,5'-Tetraiodothyroacetic ac id prevented the effect of T-4 but not of milrinone. The effects of T- 4 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 T -4 was blocked by genistein, a tyrosine kinase inhibitor In separate m odels, milrinone was shown not to interact with nuclear TR-beta. T-4 p otentiation of the antiviral activity of IFN-gamma requires PKC, PKA, and tyrosine kinase activities but not traditional TR.