NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages

J Biol Chem. 2006 Sep 8;281(36):26041-50. doi: 10.1074/jbc.M602222200. Epub 2006 Jul 11.

Abstract

NF-kappaB/Rel is a family of transcription factors whose activation has long been linked to the production of inflammatory cytokines. Here, we studied NF-kappaB signaling in the regulation of the anti-inflammatory cytokine, interleukin-10 (IL-10). We identified a role for a single NF-kappaB family member, NF-kappaB1 (p50), in promoting the transcription of IL-10. The NF-kappaB ciselement on IL-10 proximal promoter was located to -55/-46, where p50 can homodimerize and form a complex with the transcriptional co-activator CREB-binding protein to activate transcription. The other Rel family members appear to play a negligible role in IL-10 transcription. Mice lacking p50 were more susceptible to lethal endotoxemia, and macrophages taken from p50-/- mice exhibit skewed cytokine responses to lipopolysaccharide, characterized by decreased IL-10 and increased tumor necrosis factor and IL-12. Taken together, our studies demonstrate that NF-kappaB1 (p50) homodimers can be transcriptional activators of IL-10. The reciprocal regulation of pro- and anti-inflammatory cytokine production by NF-kappaB1 (p50) may provide potential new ways to manipulate the innate immune response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • CREB-Binding Protein / metabolism
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dimerization
  • Gene Expression Regulation*
  • Genes, Reporter
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Lipopolysaccharides / immunology
  • Macrophages / cytology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • NF-kappa B p50 Subunit / chemistry*
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Quaternary*
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Signal Transduction / physiology*
  • Transcription, Genetic

Substances

  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B p50 Subunit
  • Protein Subunits
  • Interleukin-10
  • CREB-Binding Protein