Protein synthesis-dependent potentiation by thyroxine of antiviral activity of interferon-g

Lin, Hung-Yun, Paul M. Yen, Faith B. Davis, and Paul J. Davis. Protein synthesis-dependent potentiation by thyroxine of antiviral activity of interferon-g. Am. J. Physiol. 273 (Cell Physiol. 42): C1225–C1232, 1997.—We have studied the prenuclear signal transduction pathway by which thyroid hormone potentiates the antiviral activity of human interferon-g (IFN-g) 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), 3,5,38-Ltriiodothyronine (T3), and milrinone enhanced the antiviral activity of IFN-g up to 100-fold, a potentiation blocked by cycloheximide. The 58-deiodinase inhibitor 6-n-propyl-2thiouracil did not block the T4 effect. 3,38,5,58-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-b. T4 potentiation of the antiviral activity of IFN-g requires PKC, PKA, and tyrosine kinase activities but not traditional TR.