Roles of phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase in the regulation of protein kinase C-alpha activation in interferon-gamma-stimulated macrophages

Immunology. 2009 Sep;128(1 Suppl):e652-60. doi: 10.1111/j.1365-2567.2009.03055.x. Epub 2009 Jan 23.


Members of the protein kinase C (PKC) family are activated by interferon-gamma (IFN-gamma) and modulate IFN-gamma-induced cellular responses by regulating the activity of transcription factors. We previously reported that PKC-alpha enhances the ability of IFN regulatory factor-1 to transactivate the class II transactivator (CIITA) promoter IV in IFN-gamma-stimulated macrophages. In addition, we showed that IFN-gamma induces the nuclear translocation of PKC-alpha but the mechanisms for this remain to be elucidated. In this study, we sought to identify signalling pathways involved in IFN-gamma-induced activation of PKC-alpha and to characterize their potential roles in modulating IFN-gamma-induced responses in macrophages. IFN-gamma-mediated nuclear translocation of PKC-alpha was a Janus activated kinase 2 (JAK2)-independent process, which required phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK). However, PKC-alpha phosphorylation was independent of PI3K and p38 MAPK, indicating that IFN-gamma-induced phosphorylation and nuclear translocation of PKC-alpha are mediated by distinct mechanisms. In addition, inhibition of PI3K, but not of p38 MAPK, strongly impaired IFN-gamma-induced CIITA and MHC II gene expression. Finally, PKC-alpha associated with signal transducer and activator of transcription 1 (STAT1) and was required for the phosphorylation of STAT1 on serine 727 in IFN-gamma-stimulated macrophages. Taken together, our data indicate that PI3K and p38 MAPK modulate IFN-gamma-stimulated PKC-alpha nuclear translocation independently of JAK2 activity and that both PI3K and PKC-alpha are required for type IV CIITA and MHC II gene expression in IFN-gamma-stimulated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / enzymology*
  • Chromones / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Female
  • Imidazoles / pharmacology
  • Interferon-gamma / pharmacology
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Morpholines / pharmacology
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Kinase C-alpha / antagonists & inhibitors
  • Protein Kinase C-alpha / metabolism*
  • Pyridines / pharmacology
  • STAT1 Transcription Factor / drug effects
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism
  • Tyrphostins / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Chromones
  • Enzyme Inhibitors
  • Imidazoles
  • MHC class II transactivator protein
  • Morpholines
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Interferon-gamma
  • Janus Kinase 2
  • Protein Kinase C-alpha
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580