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Mol. Cell. Biol. doi:10.1128/MCB.00611-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CD40 induces antigen transporter and immunoproteasome gene expression in carcinomas via the coordinated action of NF-B and of NF-B mediated de novo synthesis of IRF-1

Molecular & Cellular Biology Laboratory, and Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Crete, Greece; Institute for Molecular Biology & Biotechnology, Foundation of Research & Technology Hellas, Heraklion, Crete, Greece

^* To whom correspondence should be addressed. Email: eliopag{at}med.uoc.gr.

	Abstract

Cancer cells may evade immune surveillance as a result of defective antigen processing and presentation. In this study we demonstrate that CD40 ligation overcomes this defect through the coordinated action of the transcription factors NF-B and interferon regulatory factor-1 (IRF-1). We show that unlike interferon signaling which triggers the STAT1-mediated transcriptional activation of IRF-1, ligation of CD40 in carcinomas induces the rapid up-regulation of IRF-1 in a STAT1 independent but NF-B dependent manner. Transcriptional activation of IRF-1 is largely controlled by the recruitment of p65 (RelA) NF-B to the IRF-1 promoter following engagement of a TAK1/IKK/IB signaling pathway downstream of CD40. NF-B and de novo synthesized IRF-1 converge to regulate the expression of genes involved in antigen processing and transport, as evident by their sequential recruitment to the promoters of Transporter for Antigen Processing (TAP)-1, TAP2, tapasin and of Low Molecular Mass Polypeptides LMP2 and LMP10. Moreover, the RNAi-mediated knock-down of IRF-1 reduced, whereas inhibition of NF-B abolished the effects of CD40 on TAP1 and LMP2 up-regulation in carcinoma cells. Collectively, these data reveal a novel ‘feed-forward' mechanism induced by NF-B which ensures that acutely synthesized IRF-1 operates in concert with NF-B to amplify the immunoproteasome and antigen processing functions of CD40.