Introduction: Failure of IL-10 to keep the production of proinflammatory mediators under control is well known to represent a condition for perpetuating immune activation, which ultimately may lead to chronic inflammatory pathologies. The establishment of such vicious circle is well represented in chronic obstructive pulmonary disease (COPD), a progressive, debilitating, and often fatal, disease, characterized by an abnormal and persistent airway inflammation, continuous migration of leukocytes and chronic production of proinflammatory cytokines such as CXCL8. In COPD, the production of CXCL8, escapes the physiological negative control, despite of the high IL-10 levels detected in bronchial biopsies of these patients. This observation suggests that either the degree of cellular activation overcomes the inhibitory capability of IL-10 or a defect in the suppressive mechanisms of IL-10 has developed. Objective: To identify, by ChIP assay, the mechanisms through which IL-10 suppresses LPS-induced CXCL8 transcription, which might be defective under pathological conditions. Results: We find that IL-10 selectively controls CXCL8 transcript elongation via HDAC2-dependent covalent chromatin modifications, disrupting the assembly of the transcriptional machinery. Most importantly, the reduced intracellular levels of HDAC2 in PBMCs from acute phase COPD patients is responsible of a reduced responsiveness of these cells to IL-10- mediated inhibition of CXCL8 transcription. Conclusions: This study provides a mechanistic evidence that IL-10 creates a chromatin environment that decreases the transcriptional rate of CXCL8 to TLR4-activating signals. Data identify novel molecular targets for therapeutic strategies aimed at dampening inflammation in pathologies such as COPD, in which reduced intracellular HDAC2 levels have been described.
|Titolo:||Histone deacetylase 2 couples Interleukin-10 anti-inflammatory activity with Interleukin-8 transcriptional repression: implication for Chronic obstructive pulmonary disease patients|
|Data di pubblicazione:||2015|
|Appare nelle tipologie:||04.02 Abstract in Atti di convegno|