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

作者：Tamassia Nicola; Castellucci Monica; Rossato Marzia; Gasperini Sara; Bosisio Daniela; Giacomelli Mauro; Badolato Raffaele; Cassatella Marco A; Bazzoni Flavia^*

来源：The FASEB Journal, 2010, 24(5): 1365-1375.

DOI：10.1096/fj.09-145573

• chromatin modification
• inflammation
• neutrophils
• monocytes
• transcription

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-kappa Bp65 and NF-kappa Bp50 proteins accumulate into the nuclei and bind to the I kappa B alpha promoter during LPS stimulation, they are not recruited to the kappa B 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-kappa Bp65 and NF-kappa Bp50 to the IL-1ra promoter efficiently occurs in a STAT-3-dependent manner. Accordingly, in neutrophils from hyper-IgE syndrome patients, who carry a nonfunctional STAT3, IL-10 failed to promote NF-kappa Bp65 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-kappa B.-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-kappa B recruitment to the IL-1ra promoter that is impaired in STAT3 functionally defective patients. FASEB J. 24, 1365-1375 (2010). www.fasebj.org

• 出版日期2010-5