Abstract
Interferon (IFN)-γ is a potent activator of macrophages, increasing the cells capacity to perform specific functions during inflammation and immune response. In this report we use IFN-γ-induced upregulation of the high affinity receptor for IgG (FcγRI/CD64) in the human monocytic cell line U-937 as a model for monocytic activation. We show that upregulation of FcγRI is dependent on signals mediated by the dsRNA-dependent kinase PKR, and the transcription factor NFκB. Silencing of PKR expression by siRNA or inhibition of PKR by 2-aminopurine (2-AP) potently blocks the IFN-γ-induced transcriptional activation of the FcγRI promoter. We find that the serine 727 phosphorylation of Stat1, required for full IFN-γ-induced FcγRI promoter activity, is dependent on PKR. We further show that IFN-γ induction of FcγRI upregulation is dependent on the NFκB pathway, as evidenced by inhibition of NFκB using a phosphorylation defective IκBα (S32A/S36A) mutant, or inhibiting the IκB-kinase (IKK) by treatment with BMS345541. Our results suggest that IFN-γ-induced increase of FcγRI expression requires the integration of two signalling events: PKR-dependent Stat1 serine 727 phosphorylation, and activation of NFκB.
Published Version
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