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

J Immunol. 2007 Jun 1;178(11):6777-88. doi: 10.4049/jimmunol.178.11.6777.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Transformed
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Cytokines / physiology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Gene Expression Regulation / immunology*
  • Humans
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology*
  • Lymphocyte Activation / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / physiology*
  • Protein Subunits / physiology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / pathology
  • Toll-Like Receptors / physiology


  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • Protein Subunits
  • Toll-Like Receptors