Peroxisome Proliferator-Activated Receptor α (PPARα) down-regulation in cystic fibrosis lymphocytes

Veerle Reynders,Joachim Bargon,Dieter Steinhilber,Constanze Steinhauer,Thomas Wagner,Stefan Loitsch

doi:10.1186/1465-9921-7-104

Veerle Reynders, Joachim Bargon + Show 4 more

Open Access

https://doi.org/10.1186/1465-9921-7-104

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Abstract

BackgroundPPARs 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.MethodsPPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay.ResultsIn lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα 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 PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit.ConclusionLymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF.

Highlights

Peroxisome Proliferator-Activated Receptors α and γ (PPARs) exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response
cystic fibrosis (CF) morbidity and mortality are mainly due to lung disease, which is characterized by an excessive host inflammatory response
PPAR mRNA expression in peripheral blood cells In order to check for differences in the expression of PPARs between CF patients and healthy persons, we started screening at mRNA level

Summary

Introduction

PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. PPARs regulate gene expression by heterodimerization with the retinoid × receptor (RXR) and subsequent binding to specific DNA sequence elements, termed PPAR response elements (PPRE), in the promoter regions of their target genes [11] They can repress gene transcription in a DNA-binding independent manner through inhibition of other signaling pathways by protein-protein interactions and cofactor competition [6,7,12]. PPARα and γ agonists decrease plasma concentrations of cytokines and acute phase proteins [13,14,15] and induce anti-atherosclerotic effects [16,17] and are able to influence the immune response They seem to play a role in airway inflammation. PPARα and γ agonists have been reported to inhibit airway inflammation in a murine model of asthma [18] and a model of airway infection [19] by inhibiting eosinophil, lymphocyte and neutrophil influx into the lung

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