Phosphoinositide 3-kinase regulation of T cell receptor-mediated interleukin-2 gene expression in normal T cells.
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.
Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892-1152, USA.
A M
AM
Eder
L
L
Dominguez
T F
TF
Franke
J D
JD
Ashwell
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D007376:Interleukin-2 / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D048369:MAP Kinase Kinase 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D007376:Interleukin-2; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C482127:Map2k1 protein, mouse