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

Thyroid hormone [L-thyroxine (T₄)] 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 T₄ and agarose-T₄, 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 STAT1α by T₄; they also showed reduced T₄ potentiation of the antiviral action of interferon-γ (IFN-γ). T₄ treatment caused tyrosine-phosphorylated MAPK-STAT1α nuclear complex formation and enhanced Ser-727 phosphorylation of STAT1α, in the presence or absence of IFN-γ. STAT1α-deficient cells transfected with STAT1α containing an alanine-for-serine substitution at residue 727 (STAT1α(A727)) showed minimal T₄-stimulated STAT1α activation. IFN-γ induced the antiviral state in cells containing wild-type STAT1. (STAT1α(wt)) or STAT1α(A727); T₄ potentiated IFN-γ action in STAT1α(wt) cells but not in STAT1α(A727) cells. T₄-directed STAT1α Ser-727 phosphorylation is MAPK mediated and results in potentiated STAT1α activation and enhanced IFN-γ activity.