Activation of the p38 mitogen-activated protein kinase by type I interferons

The p38 mitogen-activated protein (Map) kinase plays a critical role in the generation of signals in response to stress stimuli, but its role in inter feron (IFN) signaling and its potential regulatory role in the activation o f Jak-signal transducer and activator of transcription (Stat) pathway are n ot known. In the present study, we provide evidence that the p38 Map kinase is rapidly phosphorylated and activated during treatment of cells with Typ e I interferons (IFN alpha and IFN beta). Furthermore, the Type I IFN-depen dent activation of p38 regulates induction of the catalytic domains of MapK ap kinase-2 and MapKap kinase-3, strongly suggesting the existence of an IF N alpha signaling cascade activated downstream of the p38 kinase. The engag ement of this pathway in interferon signaling plays a critical role in inte rferon-dependent transcriptional regulation, as evidenced by the fact that inhibition of p38 activation results in abrogation of interferon-dependent gene transcription via interferon-stimulated response elements. Interesting ly, inhibition of the kinase activity of the p38 blocks IFN alpha-induced g ene transcription without inhibiting DNA binding or tyrosine phosphorylatio n of Stat proteins, suggesting that the p38 pathway acts in cooperation wit h the Stat pathway. Thus, the p38 kinase signaling cascade is activated by the Type I interferon receptor and plays a critical role in interferon sign aling and interferon-dependent transcriptional regulation.