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Distinct Roles of Different NF-B Subunits in Regulating Inflammatory and T Cell Stimulatory Gene Expression in Dendritic Cells¹

Junmei Wang^*, Xingyu Wang^*, Sofia Hussain^*, Ye Zheng, Shomyseh Sanjabi, Fatah Ouaaz and Amer A. Beg^2,*

^* Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612; Department of Immunology, University of Washington, Seattle, WA 98195; Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and Département de Biologie Cellulaire, Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 567, Paris, France

TLRs play a critical role in inducing inflammatory and immune responses against microbial agents. In this study, we have investigated the role of NF-B transcription factors in regulating TLR-induced gene expression in dendritic cells, a key APC type. The p50 and cRel NF-B subunits were found to be crucial for regulating genes important for dendritic cell-induced T cell responses (e.g., CD40, IL-12, and IL-18) but not for genes encoding inflammatory cytokines (e.g., TNF-, IL-1, and IL-6). In striking contrast, the RelA subunit was crucial for expression of inflammatory cytokine genes but not T cell stimulatory genes. These novel findings reveal a fundamentally important difference in biological function of genes regulated by different NF-B subunits. Focusing on RelA target gene specificity mechanisms, we investigated whether the B site and/or the unique composition of RelA played the most crucial role. Surprisingly, studies of IL-6 expression showed that the B site is not a primary determinant of RelA target gene specificity. Instead, a major specificity mechanism is the unique ability of RelA to interact with the transcriptional coactivator CREB-binding protein, a function not shared with the closely related cRel subunit. Together, our findings indicate novel and critically important overall roles of NF-B in TLR-induced gene expression that are mediated by unique functions of distinct subunits.

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 by National Institutes of Health Grant R01 AI059715 and institutional funds from Moffitt Cancer Center (to A.A.B.).

² Address correspondence and reprint requests to Dr. Amer Beg, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: amer.beg{at}moffitt.org

³ Abbreviations used in this paper: DC, dendritic cell; CBP, CREB-binding protein; MEF, mouse embryonic fibroblast; BMDC, bone marrow-derived DC; BMM, bone marrow-derived macrophage; RPA, ribonuclease protection assay; IC, inflammatory cytokine; TK, thymidine kinase; ChIP, chromatin immunoprecipitation; RSV, Rous sarcoma virus; TD, transactivation domain.

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