CD40 Induces Antigen Transporter and Immunoproteasome Gene Expression in Carcinomas via the Coordinated Action of NF-κB and of NF-κB-Mediated De Novo Synthesis of IRF-1
- 1 October 2008
- journal article
- research article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 28 (20), 6208-6222
- https://doi.org/10.1128/mcb.00611-08
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-kappa B and interferon regulatory factor 1 (IRF-1). We show that unlike interferon signaling, which triggers the STAT1-mediated transcriptional activation of IRF-1, the ligation of CD40 in carcinomas induces the rapid upregulation of IRF-1 in a STAT1-independent but NF-kappa B-dependent manner. The transcriptional activation of IRF-1 is controlled largely by the recruitment of p65 (RelA) NF-kappa B to the IRF-1 promoter following the engagement of a TAK1/I kappa B kinase beta/I kappa B alpha signaling pathway downstream of CD40. NF-kappa B and de novo-synthesized IRF-1 converge to regulate the expression of genes involved in antigen processing and transport, as evident from the sequential recruitment of NF-kappa B and IRF-1 to the promoters of the genes encoding transporter for antigen processing 1 (TAP1), TAP2, tapasin, and low-molecular-mass polypeptides LMP2 and LMP10. Moreover, the RNA interference-mediated knockdown of IRF-1 reduced, whereas the inhibition of NF-kappa B abolished, the effects of CD40 on TAP1 and LMP2 upregulation in carcinoma cells. Collectively, these data reveal a novel "feed-forward" mechanism induced by NF-kappa B which ensures that acutely synthesized IRF-1 operates in concert with NF-kappa B to amplify the immunoproteasome and antigen-processing functions of CD40.Keywords
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