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 effects, whose role in
COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of
COPD patients, via both reduced 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 down-regulated PPARγ and activated NF-κB. CSE also down-regulated and post-translationally inhibited the
glucocorticoid receptor (GR-α) and
histone deacetylase 2 (HDAC2), a
corepressor important for
glucocorticoid action and whose down-regulation is thought to cause
glucocorticoid insensitivity in
COPD. Treating epithelial cells with synthetic (
rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly up-regulated 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 down-regulation 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.