Downregulated Peroxisome Proliferator-activated Receptor {gamma} (PPAR{gamma}) in Lung Epithelial Cells Promotes a PPAR{gamma} Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD) [Cell Biology]

December 24th, 2013 by Lakshmi, S. P., Reddy, A. T., Zhang, Y., Sciurba, F. C., Mallampalli, R. K., Duncan, S. R., Reddy, R. C.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory actions, whose role in COPD is largely unknown. We found that PPARγ was downregulated in lung tissue and epithelial cells of COPD patients, via both reduced gene expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor κB (NF-κB) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise downregulated PPARγ and activated NF-κB. CSE also downregulated and post-translationally inhibited the glucocorticoid receptor (GR-α) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose downregulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly upregulated PPARγ expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-κB by inhibiting the IκB kinase pathway and by promoting direct inhibitory binding of PPARγ to NF-κB. In contrast, PPARγ knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPARγ. The results imply that downregulation of pulmonary epithelial PPARγ by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPARγ agonists may be useful for COPD treatment.
  • Posted in Journal of Biological Chemistry, Publications
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