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IFN- Induces gp91^phox Expression in Human Monocytes via Protein Kinase C-Dependent Phosphorylation of PU.1¹

Paola Mazzi^*, Marta Donini^*, Daniela Margotto^*, Frans Wientjes and Stefano Dusi^2,*

^* Department of Pathology, Section of General Pathology, University of Verona, Verona, Italy; and Department of Medicine, University College London, The Rayne Institute, London, United Kingdom

We previously reported that the stimulation of human blood monocytes with IFN- induces the binding of PU.1 to the gp91^phox promoter and the consequent expression of gp91^phox. In this study, we show that the effect of IFN- is reproduced by the serine phosphatase inhibitor, okadaic acid, and this suggests that serine kinases could be involved in gp91^phox expression. We also show that IFN- induces the serine/threonine phosphorylation of PU.1 in cultured monocytes. This phosphorylation, as well as the IFN--induced PU.1 binding and gp91^phox protein synthesis, is slightly affected by the casein kinase II inhibitor, daidzein, but is abrogated by the protein kinase C (PKC) - and - inhibitor, Go6976, and by synthetic peptides with sequences based on the endogenous pseudosubstrate region of the classical PKC and isoforms. In contrast, peptides reproducing the pseudosubstrate region of PKC were without effect. Moreover, we found that the treatment of monocytes with IFN- induces the nuclear translocation and the activation of PKC and I, but not of PKC II, and that the IFN--induced phosphorylation of PU.1 was greatly reduced by LY333531, a selective inhibitor of PKC isoforms. Finally, nuclear run-on assays demonstrated that while the PKC inhibitors, Go6976 and LY333531, decrease the IFN--induced gp91^phox transcription, the serine phosphatase inhibitor, okadaic acid, enhances the gp91^phox gene transcription. Our results indicate that in cultured monocytes, IFN- induces the binding of PU.1 to the gp91^phox promoter and the expression of gp91^phox by phosphorylation of PU.1 via activation of PKC and/or I.

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