Fas apoptosis inhibitory molecule expression in B cells is regulated through IRF4 in a feed-forward mechanism.
Fas apoptosis inhibitory molecule (FAIM) was originally cloned as an inhibitor of Fas-mediated apoptosis in B cells that has been reported to affect multiple cell types. Recently, we found that FAIM enhances CD40L-mediated signal transduction, including induction of IFN regulatory factor (IRF)4, in vitro and augments plasma cell production in vivo. These results have keyed interest in the regulation of FAIM expression, about which little is known. Here, we show that Faim is regulated by IRF4. The Faim promoter contains three IRF binding sites, any two of which promote Faim expression. Faim promoter activity is lost following mutation of all three IRF binding sites, whereas activity of the full promoter is enhanced by concurrent expression of IRF4. In stimulated primary B cells, IRF4 expression precedes FAIM expression, IRF4 binds directly to the Faim promoter, and loss of IRF4 results in the failure of stimulated Faim up-regulation. Finally, FAIM is preferentially expressed in germinal center B cells. Taken together, these results indicate that FAIM expression is regulated through IRF4 and that this most likely occurs as part of germinal center formation. Because FAIM enhances CD40-induced IRF4 expression in B cells, these results suggest that induction of FAIM initiates a positive reinforcing (i.e., feed-forward) system in which IRF4 expression is both enhanced by FAIM and promotes FAIM expression.
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
Hiroaki
H
Kaku
Thomas L
TL
Rothstein
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016384:Consensus Sequence / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000502:physiology; D000099218:Interferon Regulatory Factor-4
D051017:Apoptosis Regulatory Proteins; D050835:Interferon Regulatory Factors; D019014:fas Receptor; D000099218:Interferon Regulatory Factor-4; C498892:Faim protein, mouse