PI 3 kinase-dependent Akt kinase and PKCε independently regulate interferon-γ-induced STAT1α serine phosphorylation to induce monocyte chemotactic protein-1 expression

Balachandar A. Venkatesan, Lenin Mahimainathan, Nandini Ghosh-Choudhury, Yves Gorin, Basant Bhandari, Anthony J. Valente, Hanna E. Abboud, Goutam Ghosh Choudhury

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Monocyte chemotactic protein-1 (MCP-1) recruits activated phagocytes to the site of tissue injury. Interferon-γ (IFN-γ) present in the microenvironment of glomerulus acts on mesangial cells to induce local production of MCP-1. The mechanism by which IFN-γ stimulates expression of MCP-1 is not clear. We therefore examined the role of PI 3 kinase signaling in regulating the IFN-γ-induced MCP-1 expression in mesangial cells. Blocking PI 3 kinase activity with Ly294002 attenuated IFN-γ-induced MCP-1 protein and mRNA expression. IFN-γ increased Akt kinase activity in a PI 3 kinase-dependent manner. Expression of dominant negative Akt kinase inhibited serine phosphorylation of STAT1α, without any effect on its tyrosine phosphorylation, and decreased IFN-γ-induced expression of MCP-1. These data for the first time indicate a role for PI 3 kinase-dependent Akt kinase in MCP-1 expression. We have recently shown that along with Akt, PKCε is a downstream target of PI 3 kinase in IFN-γ signaling. Similar to dominant negative Akt kinase, dominant negative PKCε also inhibited serine phosphorylation of STAT1α without any effect on tyrosine phosphorylation. Dominant negative PKCε also abrogated MAPK activity, resulting in decrease in IFN-γ-induced MCP-1 expression. Furthermore, Akt and PKCε are present together in a signaling complex. IFN-γ had no effect on this complex formation, but did increase PKCε-associated Akt kinase activity. PKCε did not regulate IFN-γ-induced Akt kinase. Finally, expression of dominant negative Akt kinase blocked IFN-γ-stimulated MAPK activation. These data provide the first evidence that PI 3 kinase-dependent Akt and PKCε activation independently regulate MAPK activity and serine phosphorylation of STAT1α to increase expression of MCP-1.

Original languageEnglish (US)
Pages (from-to)508-518
Number of pages11
JournalCellular Signalling
Volume18
Issue number4
DOIs
StatePublished - Apr 1 2006

Keywords

  • MCP-1
  • Mesangial cell
  • PI 3 kinase
  • PKC-epsilon
  • STAT1-alpha

ASJC Scopus subject areas

  • Cell Biology

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