Background and aims The role of Phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and dexamethasone in IFN-α-induced-human interferon-induced protein with tetratricopeptide repeats 4 (IFIT4) expression was investigated.
Methods HT1080 cells were pre-treated with specific inhibitors of PI3K/mTOR, PKC or JNK transduction factors, then further incubated with IFN-α for different times. The mRNA and protein expression of IFIT4 or other indicated signal transduction factors were detected by qRT-PCR or western-blot.
Results LY294002, a dual mTOR and PI3K inhibitor, but not wortmannin, blocked IFIT4 promoter activation, mRNA and protein, as well as phosphorylation of STAT1, JNK, PKCδ induced by IFN-α. Interestingly, rapamycin, mTOR inhibitor, had the same effects as LY294002, counteracting the IFN-α-dependent upregulation of IFIT4 and phosphorylation of STAT1, JNK, PKCδ. Rottlerin or Sp600125, specific inhibitor of PKCδ, JNK, inhibited IFN-induced IFIT4 expression, but not the phosphorylation of AKT and mTOR. Interestingly, in vivo, bolus intravenous injection of methylprednisolone rapidly decreased the IFIT4 expression. In vitro, dexamethasone could prohibit IFN-α-induced IFIT4 transcription and the phosphorylation of STAT1, JNK, PKC-δ.
Conclusions IFN-α activate the PI3K and mTOR pathways, which converge to regulate PKCδ, JNK , STAT1-dependent transcription of IFIT4 in a mTOR dependent and AKT independent manner. The induction of IFIT4 transcription by IFN-α depends upon sequential activation of mTOR, PKCδ, JNK and STAT1. Steriod might play the role in treatment for systemic lupus erythematosus (SLE) partially by the reason of decreasing IFN alpha induced protein IFIT4 expression via sequential inhibition of the phosphorylation of PI3K, mTOR, PKCδ, JNK, STAT1.
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