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


METHODS
BAL cells were analyzed for PPARgamma and IFN-gamma mRNA expression by quantitative PCR and for PPARgamma protein by immunocytochemistry and western blotting.


RESULTS
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.


CONCLUSIONS
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.
Barna
Barbara P
BP
Department of Pulmonary, Allergy, and Critical Care Medicine, Lerner Research Institute, The Cleveland Clinic Foundation, OH 44195, USA.
Culver
Daniel A
DA
Abraham
Susamma
S
Malur
Anagha
A
Bonfield
Tracey L
TL
John
Nejimole
N
Farver
Carol F
CF
Drazba
Judith A
JA
Raychaudhuri
Baisakhi
B
Kavuru
Mani S
MS
Thomassen
Mary Jane
MJ
D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D017565:Sarcoidosis, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index
D015415:Biomarkers; D047495:PPAR gamma; D012333:RNA, Messenger; D007371:Interferon-gamma