Uncovering an IL-10-dependent NF-kappaB recruitment to the IL-1ra promoter that is impaired in STAT3 functionally defective patients.
The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. Using chromatin immunoprecipitation, we show that although NF-kappaBp65 and NF-kappaBp50 proteins accumulate into the nuclei and bind to the IkappaB alpha promoter during LPS stimulation, they are not recruited to the kappaB sites of the IL-1ra promoter. However, in response to LPS plus IL-10, which were found to induce chromatin acetylation, recruitment of both NF-kappaBp65 and NF-kappaBp50 to the IL-1ra promoter efficiently occurs in a STAT3-dependent manner. Accordingly, in neutrophils from hyper-IgE syndrome patients, who carry a nonfunctional STAT3, IL-10 failed to promote NF-kappaBp65 recruitment to the IL-1ra promoter and consequently to potentiate LPS-induced IL-1ra transcription. Altogether our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB.
Tamassia
Nicola
N
Department of Pathology, Division of General Pathology, University of Verona, Strada le Grazie 8, Verona, Italy.
Castellucci
Monica
M
Rossato
Marzia
M
Gasperini
Sara
S
Bosisio
Daniela
D
Giacomelli
Mauro
M
Badolato
Raffaele
R
Cassatella
Marco A
MA
Bazzoni
Flavia
F
D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000328:Adult; D047369:Chromatin Immunoprecipitation; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides; D009000:Monocytes / Q000276:immunology; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D055815:Young Adult
C508609:IL10 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051996:Transcription Factor RelA; D016753:Interleukin-10