Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50.
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.
Driessler
F
F
Research Business Area Dermatology, Research Laboratories of Schering AG, Berlin, Germany.
Venstrom
K
K
Sabat
R
R
Asadullah
K
K
Schottelius
A J
AJ
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics*; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D051996:Transcription Factor RelA; D014178:Translocation, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10