A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis.
Apoptosis is a highly regulated process of cell suicide that occurs during development, host defense, and pathophysiology. The transcription factor IFN regulatory factor 5 (IRF5), known to be involved in the activation of innate immune responses, recently has been shown to be critical for DNA damage-induced apoptosis and tumor suppression. Here, we report on a cell-type-specific role of IRF5 in promoting apoptosis upon signaling through the death receptor Fas (CD95/APO-1/TNFRSF6). In particular, we show that mice deficient in the Irf5 gene are resistant to hepatic apoptosis and lethality in response to the in vivo administration of a Fas-activating monoclonal antibody, and that IRF5 is involved in a stage of Fas signaling that precedes the activation of caspase 8 and c-Jun N-terminal kinase (JNK). In addition to hepatocytes, IRF5 is also required for apoptosis in dendritic cells activated by hypomethylated CpG but not in thymocytes and embryonic fibroblasts in vitro. Thus, these findings reveal a cell-type-specific function for IRF5 in the complex regulatory mechanism of death-receptor-induced apoptosis.
Couzinet
Arnaud
A
Departments of Immunology and Molecular Pathology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Tamura
Kaoru
K
Chen
Hui-Min
HM
Nishimura
Keishiro
K
Wang
Zhichao
Z
Morishita
Yasuyuki
Y
Takeda
Kazuyoshi
K
Yagita
Hideo
H
Yanai
Hideyuki
H
Taniguchi
Tadatsugu
T
Tamura
Tomohiko
T
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012680:Sensitivity and Specificity; D019014:fas Receptor / Q000378:metabolism*
D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases