Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL.
Apoptosis is an integral aspect of B lymphocyte development and homeostasis and is regulated by the engagement of antigen costimulatory and cytokine receptors. Although it is well established that interleukin 4 (IL-4) is a potent anti-apoptotic cytokine for B lymphocytes, little is known about the IL-4-induced molecular events regulating cell survival. Stat6 is rapidly activated after IL-4 stimulation, but its role in B lymphocyte apoptosis has not been explored. In this report we demonstrate that Stat6 is a critical signaling molecule for IL-4 in protecting primary B cells from passive and Fas-induced cell death. We show that expression of the Bcl-2 family member, Bcl-xL, is induced maximally by IL-4 and anti-IgM/IL-4 in a Stat6-dependent manner. Additionally, we demonstrate that bcl-xL transcription is likely to be directly activated through a Stat6 binding site in the bcl-xL-flanking region. Finally, reconstitution of Stat6-deficient splenic B cells with Bcl-xL was able to protect those cells from Fas-induced cell death. These results suggest that the anti-apoptotic activity of IL-4 in B cells is mediated through the activation of Stat6 and subsequent transcription of Bcl-xL.
Wurster
Andrea L
AL
Department of Immunology and Infectious Diseases, School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
Rodgers
Vikki L
VL
White
Morris F
MF
Rothstein
Thomas L
TL
Grusby
Michael J
MJ
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D015152:Blotting, Northern; D016923:Cell Death; D002478:Cells, Cultured; D015151:Immunoblotting; D015847:Interleukin-4 / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D011419:Propidium / Q000494:pharmacology*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D051020:bcl-X Protein; D015847:Interleukin-4; D011419:Propidium; D008156:Luciferases