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Published ahead of print on September 25, 2003, doi:10.1165/rcmb.2003-0304RC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 1, January 2004, 1-5

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Submitted on August 19, 2003
Revised on September 25, 2003

PPAR{gamma} activity is deficient in alveolar macrophages in pulmonary sarcoidosis

Daniel A Culver1, Barbara P Barna1, Baisakhi Raychaudhuri1, Tracey L Bonfield1, Susamma Abraham1, Anagha Malur1, Carol F Farver2, Mani S Kavuru1, and Mary Jane Thomassen3*

1 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA, 2 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA, 3 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA

* To whom correspondence should be addressed. E-mail: thomasm{at}ccf.org.

The ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPAR{gamma}) has pleiotropic effects on lipid and glucose metabolism as well as modulating immune activity. In Th1-predominant models of inflammatory bowel disease and arthritis, PPAR{gamma} ligands can ameliorate clinical disease severity, partly by down-regulating a range of inflammatory cytokines. However, PPAR{gamma} has not been evaluated in chronic sarcoidosis, a disease characterized by persistent activation of Th1 immune responses in alveolar macrophages. We hypothesized that a deficiency of PPAR{gamma} activity contributes to ongoing inflammation in pulmonary sarcoidosis via failure to repress proinflammatory transcription factors. To address this, we studied 8 patients with active sarcoidosis and 9 healthy controls by bronchoscopy. Bronchoalveolar lavage specimens from patients revealed a striking reduction of PPAR{gamma} activity by electrophoretic mobility shift assay in alveolar macrophages compared to healthy controls, with a concomitant upregulation of NF-{kappa}B activity. Immunostaining and real-time PCR demonstrated reductions of PPAR{gamma} nuclear protein and gene expression. The data show for the first time that alveolar macrophages from patients with active sarcoidosis exhibit activation of NF-{kappa}B and deficiency of PPAR{gamma}. Although these results do not demonstrate a direct causal effect, they are consistent with the hypothesis that insufficient PPAR{gamma} activity contributes to ongoing dysregulated inflammation in pulmonary sarcoidosis by failing to suppress NF-{kappa}B.




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