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J Immunol. 2007 Jun 1;178(11):6777-88.

Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells.

Author information

1
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.

Abstract

TLRs play a critical role in inducing inflammatory and immune responses against microbial agents. In this study, we have investigated the role of NF-kappaB transcription factors in regulating TLR-induced gene expression in dendritic cells, a key APC type. The p50 and cRel NF-kappaB 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-alpha, IL-1alpha, 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-kappaB subunits. Focusing on RelA target gene specificity mechanisms, we investigated whether the kappaB site and/or the unique composition of RelA played the most crucial role. Surprisingly, studies of IL-6 expression showed that the kappaB 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-kappaB in TLR-induced gene expression that are mediated by unique functions of distinct subunits.

PMID:
17513725
DOI:
10.4049/jimmunol.178.11.6777
[Indexed for MEDLINE]
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