Peroxisome proliferator-activated receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes.
BACKGROUND
PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response.


METHODS
PPARalpha, beta and gamma mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARalpha protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARalpha was analyzed by gel shift assay.


RESULTS
In lymphocytes, the expression of PPARalpha mRNA, but not of PPARbeta, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARalpha was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARalpha and PPARbeta mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARgamma mRNA levels were below the detection limit.


CONCLUSIONS
Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARalpha may therefore contribute to the inflammatory processes that are observed in CF.
Reynders
Veerle
V
Dept. of Internal Medicine, Division of Pneumology, University Hospital Frankfurt, Germany. veerlereynders@hotmail.com
Loitsch
Stefan
S
Steinhauer
Constanze
C
Wagner
Thomas
T
Steinhilber
Dieter
D
Bargon
Joachim
J
D000328:Adult; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D018836:Inflammation Mediators; D047493:PPAR alpha; D012333:RNA, Messenger