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Peroxisome Proliferator–Activated Receptor Activity Is Deficient in Alveolar Macrophages in Pulmonary Sarcoidosis

Departments of Pulmonary and Critical Care Medicine, Anatomic Pathology, and Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio

Address correspondence to: Mary Jane Thomassen, Ph.D., Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue/A90, Cleveland, OH 44195. E-mail: thomasm{at}ccf.org

The ligand-activated transcription factor, peroxisome proliferator–activated receptor (PPAR), 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 ligands can ameliorate clinical disease severity, partly by downregulating a range of inflammatory cytokines. However, PPAR 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 activity contributes to ongoing inflammation in pulmonary sarcoidosis via failure to repress proinflammatory transcription factors. To address this, we studied eight patients with active sarcoidosis and nine healthy control subjects by bronchoscopy. Bronchoalveolar lavage specimens from patients revealed a striking reduction of PPAR activity by electrophoretic mobility shift assay in alveolar macrophages compared with healthy control subjects, with a concomitant upregulation of nuclear factor (NF)-B activity. Immunostaining and real-time polymerase chain reaction demonstrated reductions of PPAR nuclear protein and gene expression. The data show for the first time that alveolar macrophages from patients with active sarcoidosis exhibit activation of NF-B and deficiency of PPAR. Although these results do not demonstrate a direct causal effect, they are consistent with the hypothesis that insufficient PPAR activity contributes to ongoing dysregulated inflammation in pulmonary sarcoidosis by failing to suppress NF-B.

Abbreviations: bronchoalveolar lavage, BAL • electrophorectic mobility shift assay, EMSA • interferon, IFN • nuclear factor-B, NF-B • peroxisome proliferator–activated receptor , PPAR • peroxisome proliferator response element, PPRE • whole cell extract, WCE