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Roles of phosphatidylinositol 3‐kinase and p38 mitogen‐activated protein kinase in the regulation of protein kinase C‐α activation in interferon‐γ‐stimulated macrophages
Author(s) -
Hardy PierreOlivier,
Diallo Tamsir O.,
Matte Christine,
Descoteaux Albert
Publication year - 2009
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2009.03055.x
Subject(s) - ciita , protein kinase c , microbiology and biotechnology , stat1 , p38 mitogen activated protein kinases , biology , mapk/erk pathway , transactivation , kinase , phosphatidylinositol , protein kinase a , pi3k/akt/mtor pathway , signal transduction , mitogen activated protein kinase , cancer research , transcription factor , mhc class ii , t cell , immunology , biochemistry , immune system , gene
Summary Members of the protein kinase C (PKC) family are activated by interferon‐γ (IFN‐γ) and modulate IFN‐γ‐induced cellular responses by regulating the activity of transcription factors. We previously reported that PKC‐α enhances the ability of IFN regulatory factor‐1 to transactivate the class II transactivator ( CIITA ) promoter IV in IFN‐γ‐stimulated macrophages. In addition, we showed that IFN‐γ induces the nuclear translocation of PKC‐α but the mechanisms for this remain to be elucidated. In this study, we sought to identify signalling pathways involved in IFN‐γ‐induced activation of PKC‐α and to characterize their potential roles in modulating IFN‐γ‐induced responses in macrophages. IFN‐γ‐mediated nuclear translocation of PKC‐α was a Janus activated kinase 2 (JAK2)‐independent process, which required phosphatidylinositol 3‐kinase (PI3K) and p38 mitogen‐activated protein kinase (MAPK). However, PKC‐α phosphorylation was independent of PI3K and p38 MAPK, indicating that IFN‐γ‐induced phosphorylation and nuclear translocation of PKC‐α are mediated by distinct mechanisms. In addition, inhibition of PI3K, but not of p38 MAPK, strongly impaired IFN‐γ‐induced CIITA and MHC II gene expression. Finally, PKC‐α associated with signal transducer and activator of transcription 1 (STAT1) and was required for the phosphorylation of STAT1 on serine 727 in IFN‐γ‐stimulated macrophages. Taken together, our data indicate that PI3K and p38 MAPK modulate IFN‐γ‐stimulated PKC‐α nuclear translocation independently of JAK2 activity and that both PI3K and PKC‐α are required for type IV CIITA and MHC II gene expression in IFN‐γ‐stimulated macrophages.