Phosphoinositide 3-kinase regulation of T cell receptor-mediated interleukin-2 gene expression in normal T cells

J Biol Chem. 1998 Oct 23;273(43):28025-31. doi: 10.1074/jbc.273.43.28025.

Abstract

Phosphoinositide (PI) 3-kinase has been implicated in T cell receptor (TCR) signaling, either as a positive or a negative regulatory molecule. Here, we show that for normal mouse lymph node T cells, PI 3-kinase activity is required for interleukin-2 (IL-2) production following TCR-mediated activation. Furthermore, in normal T cells, inhibition of PI 3-kinase prevented activation of enzymes in the extracellular signal-regulated protein kinase (ERK) signaling pathway (MEK-1 and ERK-2). Overexpression of a dominant-negative mutant of PI 3-kinase and pharmacological inhibitors of PI 3-kinase prevented transcriptional activation of AP-1 and NF-AT, transcription factors regulated by ERK-2 and pivotal for IL-2 gene expression. Although a constitutively active form of Akt kinase, a downstream mediator of PI 3-kinase function, enhanced TCR-induced IL-2 gene transcription, it could not bypass the requirement for PI 3-kinase activity. Therefore, PI 3-kinase is likely to be involved in signaling for IL-2 production in at least two steps in the TCR-initiated signaling pathway.

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Chromones / pharmacology
  • Enzyme Activation
  • Female
  • Interleukin-2 / biosynthesis*
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology*
  • Lymphocyte Activation
  • MAP Kinase Kinase 1
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Transcription, Genetic
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Interleukin-2
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • Wortmannin