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Fas Apoptosis Inhibitory Molecule Expression in B Cells Is Regulated through IRF4 in a Feed-Forward Mechanism¹

Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by U.S. Public Health Service Grants AI040181 and AI083509.

² Address correspondence and reprint requests to Dr. Thomas L. Rothstein, Center for Oncology and Cell Biology (Immunobiology Laboratory), The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: tr{at}nshs.edu

³ Abbreviations used in this paper: AID, activation-induced cytidine deaminase; BCL-6, B cell lymphoma-6; ChIP, chromatin immunoprecipitation; FAIM, Fas apoptosis inhibitory molecule; FOB, follicular B cell; GCB, germinal center B cell; IRF, IFN regulatory factor; PNA, peanut agglutinin; TNP-KLH, 2,4,6-trinitrophenyl-keyhole limpet hemocyanin; WT, wild type.