Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50

Clin Exp Immunol. 2004 Jan;135(1):64-73. doi: 10.1111/j.1365-2249.2004.02342.x.


Nuclear factor kappa B (NF-kappaB) is a transcription factor pivotal for the development of inflammation. A dysregulation of NF-kappaB has been shown to play an important role in many chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although classical NF-kappaB, a heterodimer composed of the p50 and p65 subunits, has been well studied, little is known about gene regulation by other hetero- and homodimeric forms of NF-kappaB. While p65 possesses a transactivation domain, p50 does not. Indeed, p50/p50 homodimers have been shown to inhibit transcriptional activity. We have recently shown that Interleukin-10 exerts its anti-inflammatory activity in part through the inhibition of NF-kappaB by blocking IkappaB kinase activity and by inhibiting NF-kappaB already found in the nucleus. Since the inhibition of nuclear NF-kappaB could not be explained by an increase of nuclear IkappaB, we sought to further investigate the mechanisms involved in the inhibition of NF-kappaB by IL-10. We show here that IL-10 selectively induced nuclear translocation and DNA-binding of p50/p50 homodimers in human monocytic cells. TNF-alpha treatment led to a strong translocation of p65 and p50, whereas pretreatment with IL-10 followed by TNF-alpha blocked p65 translocation but did not alter the strong translocation of p50. Furthermore, macrophages of p105/p50-deficient mice exhibited a significantly decreased constitutive production of MIP-2alpha and IL-6 in comparison to wild type controls. Surprisingly, IL-10 inhibited high constitutive levels of these cytokines in wt macrophages but not in p105/p50 deficient cells. Our findings suggest that the selective induction of nuclear translocation and DNA-binding of the repressive p50/p50 homodimer is an important anti-inflammatory mechanism utilized by IL-10 to repress inflammatory gene transcription.

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Interleukin-10 / pharmacology*
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / immunology
  • Mice
  • Mice, Inbred Strains
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics*
  • NF-kappa B p50 Subunit
  • Protein Precursors / genetics
  • Recombinant Proteins / pharmacology
  • Transcription Factor RelA
  • Translocation, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology


  • Lipopolysaccharides
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Protein Precursors
  • Recombinant Proteins
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Interleukin-10