Article

Depressed peroxisome proliferator-activated receptor gamma (PPargamma) is indicative of severe pulmonary sarcoidosis: possible involvement of interferon gamma (IFN-gamma).

Department of Pulmonary, Allergy, and Critical Care Medicine, Lerner Research Institute, The Cleveland Clinic Foundation, OH 44195, USA.
Sarcoidosis, vasculitis, and diffuse lung diseases: official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders (Impact Factor: 1.74). 07/2006; 23(2):93-100.
Source: PubMed

ABSTRACT Recent evidence suggests that the transcription factor, PPARgamma, is an important negative regulator of inflammation. Because studies of murine adipocytes and macrophages implicate IFN-gamma, a key mediator of granuloma formation in sarcoidosis, as a PPARgamma antagonist, we investigated the relationship between PPARgamma and IFN-gamma in bronchoalveolar lavage (BAL) cells of sarcoidosis patients and healthy controls.
BAL cells were analyzed for PPARgamma and IFN-gamma mRNA expression by quantitative PCR and for PPARgamma protein by immunocytochemistry and western blotting.
In sarcoidosis patients with severe, treatment-requiring disease, IFN-gamma was strikingly elevated and PPARgamma gene expression was deficient. In contrast, PPARgamma expression of non-severe patients was comparable to control but was still accompanied by increased IFN-gamma. By confocal microscopy, nuclear PPARgamma protein was detectable in alveolar macrophages from non-severe patients unlike previous observations of severe patients. In vitro exposure of BAL cells or purified alveolar macrophages to IFN-gamma resulted in dose-dependent repression of PPARgamma mRNA in both sarcoidosis and controls. IFN-gamma treatment also reduced PPARgamma protein in BAL lysates and nuclear PPARgamma content in control alveolar macrophages, resulting in a diffuse cytoplasmic PPARgamma distribution similar to that observed in severe sarcoidosis.
These novel results indicate that IFN-gamma represses PPARgamma in human alveolar macrophages but that in sarcoidosis, PPARgamma rather than IFN-gamma levels correlate best with disease severity. Data also emphasize the complex nature of PPARgamma restorative mechanisms in alveolar macrophages exposed to an inflammatory environment containing IFN-gamma -- a potential PPARgamma antagonist.

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