p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons

Activation of cytosolic phospholipase A(2) (cPLA(2)) is a prerequisite for the formation of the transcription factor complex interferon-stimulated gen e factor 3 (ISGF3) in response to interferon-alpha (IFN-alpha), Here we sho w that p38 mitogen-activated protein kinase (MAPK), an activator of cPLA(2) , is essential for both IFN-alpha and IFN-gamma signalling. SB203580, a spe cific inhibitor of p38, was found to inhibit ISGF3 formation but had no app arent effects on signal transducer and activator of transcription (STAT) 1 homodimer formation. Regardless of this, the antiviral activities of both I FN-alpha and IFN-gamma were attenuated by SB203580, Treatment with either I FN Led to rapid and transient activation of p38, Both IFNs induced STAT1 Se r727 phosphorylation, which was inhibited by SB203580 but not by an extrace llular signal related kinase (ERK)1/2 inhibitor (PD98059), In an inducible 3T3-L1 clone, expression of dominant-negative p38 led to defective STAT1 se rine phosphorylation and diminished IFN-gamma-mediated protection against v iral killing. Reporter activity mediated by ISGF3 or STAT1 homodimer was di minished by SB203580 and enhanced by a constitutively active mutant of MKK6 , the upstream activator of p38, Therefore, p38 plays a key role in the ser ine phosphorylation of STAT1 and transcriptional changes induced by both IF Ns.