Peroxisome proliferator-activated receptor gamma activity is deficient in alveolar macrophages in pulmonary...

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 downregulating 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 eight patients with active sarcoidosis and nine healthy control subjects by bronchoscopy. Bronchoalveolar lavage specimens from patients revealed a striking reduction of PPAR gamma activity by electrophoretic mobility shift assay in alveolar macrophages compared with healthy control subjects, with a concomitant upregulation of nuclear factor (NF)-kappa B activity. Immunostaining and real-time polymerase chain reaction 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.