Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells.
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.
Wang
Junmei
J
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Wang
Xingyu
X
Hussain
Sofia
S
Zheng
Ye
Y
Sanjabi
Shomyseh
S
Ouaaz
Fatah
F
Beg
Amer A
AA
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D021122:Protein Subunits / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051193:Toll-Like Receptors / Q000502:physiology
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D021122:Protein Subunits; D051193:Toll-Like Receptors