Down-regulated Peroxisome Proliferator-activated Receptor γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD)

Sowmya P Lakshmi,Aravind T Reddy,Yingze Zhang,Frank C Sciurba,Rama K Mallampalli,Steven R Duncan,Raju C Reddy

doi:10.1074/jbc.m113.536805

Abstract

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.

Highlights

The mechanistic role of peroxisome proliferator-activated receptor ␥ (PPAR␥) in chronic obstructive pulmonary disease (COPD) is poorly understood
We found that PPAR␥ was Chronic obstructive pulmonary disease (COPD)2 is a prodown-regulated in lung tissue and epithelial cells of COPD gressive disease that, due to lack of effective treatment [1], is a pataetdienintsh,ivbiiatiboonTt,hhwrehidseuraecaersdteipcxrpoler-einshsfilaoamnsambnadetoperhnyosnrpuehcotlrreyaalractiftoaenctd-omrbe-␬dyiB- thlceehaapdriauncgbteclraiiuzseshedeobfryd. ecTahthrhoeinnirctihgpeuhUlmtnoiptneAdarcSyKtaint-efHslaa3mnmd watoiorlndwanidde.loItnigs (NF-␬B) activiatynwdasHin3criemasemd. uCnigaorbetltoe tsms ofkrionmg isFthieg.m6aiAn wteerrme trisesuuesdeedstriunctFioingt.h1atAimapsaiPrsPreAspRir a.tory gas exchange
We found that PPAR␥ expression and activity are down-regulated in human bronchial epithelial (HBE) cells from COPD patients and those exposed to cigarette smoke extract (CSE) in vitro, whereas proinflammatory pathways are up-regulated

Summary

Background

The mechanistic role of peroxisome proliferator-activated receptor ␥ (PPAR␥) in chronic obstructive pulmonary disease (COPD) is poorly understood. The results hormone receptor superfamily, exerts strong anti-inflammaimply that down-regulation of pulmonary epithelial PPAR␥ by tory and antioxidant effects [7, 8] by down-regulating activity of cigarette smoke promotes inflammatory pathways and dimin- nuclear factor-␬B (NF-␬B) and other pro-inflammatory transcription factors via multiple mechanisms. These findings raise the possibility that PPAR␥ agonists may be therapeutically useful for treating COPD, and may reverse COPD patients’ resistance to anti-inflammatory steroid therapy by restoring impaired HDAC2 activity

EXPERIMENTAL PROCEDURES

RESULTS

AcK-H4 H4

DISCUSSION