IL-4-dependent induction of BCL-2 and BCL-X(L)IN activated T lymphocytes through a STAT6- and pi 3-kinase-independent pathway.
Both B and T lymphocytes require ongoing signals to maintain their viability. The pleiotropic cytokine interleukin (IL-) 4 plays an important role in the maintenance of activated T cells, perhaps reflecting induction of the anti-apoptotic genes Bcl-2 and Bcl-X(L). However, it is not known which of the signalling pathways known to link the IL-4 receptor with transcription regulation are required, or if the levels of Bcl-2/X induction under such physiologic conditions are sufficient to account for the anti-apoptotic effects of IL-4. We report here that although blockade of pathways (PI 3-kinase and pp70 S6 kinase) recruited by the IRS-1/2 adaptor proteins inhibited the anti-apoptotic function of IL-4, Bcl-2/X induction were normal. These findings were recapitulated in primary and culture-adapted T cells whose Stat6 signalling pathway also was defective. These results demonstrate that both the Stat6 and PI 3-kinase pathways can be dispensable for Bcl-2/X induction by IL-4, thus suggesting the involvement of an additional signal transduction pathway. Moreover, the preservation of Bcl-2/X induction despite inhibition of the anti-apoptotic function of IL-4 indicates that this cytokine activates additional protective mechanisms.
Aronica
M A
MA
Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine, Vanderbilt University Medical School, Nashville, TN, 37232, USA.
Goenka
S
S
Boothby
M
M
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019254:Genes, bcl-2; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D019948:Receptors, Interleukin-4 / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D000077191:Wortmannin; D051020:bcl-X Protein
D000730:Androstadienes; C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D051020:bcl-X Protein; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus; D000077191:Wortmannin