Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells

Thyroid hormone [L-thyroxine (T-4)] rapidly induced phosphorylation and nuclear translocation (activation) of mitogen-activated protein kinase (MAPK) in HeLa and CV-1 cells in the absence of cytokine or growth factor. A pertussis toxin-sensitive and guanosine 5'-O-(3-thiotriphosphate)-sensitive cell surface mechanism responsive to T-4 and agarose-T-4, suggesting a G protein-coupled receptor, was implicated. Cells depleted of MAPK or treated with MAPK pathway inhibitors showed reduced activation of MAPK and of the signal transducer and activator of transcription STAT1 alpha by T-4; they also showed reduced T-4 potentiation of the antiviral action of interferon-gamma (IFN-gamma). T-4 treatment caused tyrosine-phosphorylated MAPK-STAT1 alpha nuclear complex formation and enhanced Ser-727 phosphorylation of STAT1 alpha, in the presence or absence of IFN-gamma. STAT1 alpha-deficient cells transfected with STAT1 alpha containing an alanine-for-serine substitution at residue 727 (STAT1 alpha(A727)) showed minimal T-4-stimulated STAT1 alpha activation. IFN-gamma induced the antiviral state in cells containing wild-type STAT1 alpha (STAT1 alpha(wt)) or STAT1 alpha(A727); T-4 potentiated IFN-gamma action in STAT1 alpha(wt) cells but not in STAT1 alpha(A727) cells. T-4-directed STAT1 alpha Ser-727 phosphorylation is MAPK mediated and results in potentiated STAT1 alpha activation and enhanced IFN-gamma activity.