Uncovering an IL‐10‐dependent NF‐KB recruitment to the IL‐1ra promoter that is impaired in STAT3 functionally defective patients

The interleukin 1 receptor antagonist (IL‐lra) 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‐κBp65 and NF‐κBp50 proteins accumulate into the nuclei and bind to the IKBα promoter during LPS stimulation, they are not recruited to the κB 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‐κBp65 and NF‐κBp50 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‐κBp65 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‐KB.—Tamassia, N., Castellucci, M., Rossato, M., Gasperini, S., Bosisio, D., Giacomelli, M., Badolato, R., Cassatella, M. A., Bazzoni, F. Uncovering an IL‐10‐dependent NF‐κB recruitment to the IL‐1ra promoter that is impaired in STAT3 functionally defective patients. FASEB J. 24, 1365–1375 (2010). www.fasebj.org