Regulation of lymphocyte apoptosis by interferon regulatory factor 4 (IRF-4).
To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fas-mediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4-deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4-transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4-deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis.
Fanzo
Jessica C
JC
Department of Molecular Medicine, Columbia University, New York, NY 10032, USA.
Hu
Chuan-Min
CM
Jang
So Young
SY
Pernis
Alessandra B
AB
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D050835:Interferon Regulatory Factors; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D014157:Transcription Factors; D019014:fas Receptor; D000099218:Interferon Regulatory Factor-4; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse