Differential regulation of peroxisome proliferator activated receptor (ppar) isoforms in murine macrophage J774.2 cell line by cytokines
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Date
2006
Authors
Guat Slew, Chew
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Abstract
The regulation of the PPAR isoforms in macrophage by cytokines is of
potentially crucial importance in pathophysiological disorders such as atherosclerosis.
In the present study, we evaluated the action of four cytokines on the expression of
PPAR mRNA, protein and functional PPAR-DNA binding activity in the murine
macrophage J774.2 cell line, a widely used model system for atherosclerosis.
Exposure of the cells to TNF-a and IFN-y for 24h, produced a dose-dependent
reduction of PPARa and PPARy and a dose-dependent increase of PPAR~/8 mRNA
and protein expression. In contrast, IL-1~ produced a dose-dependent increase of
PPARa and PPARy and a dose-dependent decrease in PPAR~/8 mRNA and protein
expression. However, IL-1a has no effect on all isoforms of PPAR mRNA and protein
expression. Electrophoretic mobility shift assay (EMSA) showed a close correlation
between the expression of the PPAR mRNA, protein and the functional PPAR-DNA
binding activity. Incubation of nuclear extracts with anti-PPAR antibodies in super-shift
assay demonstrated the participation of all the three PPAR isoforms'in the binding to
PPRE. These results indicate that TNF-a, IFN-y, IL-1~ and IL-1a are important
regulators of macrophage PPAR gene and protein expression which affect its DNA
binding activities. Thus, this study provides novel insights into the potential
mechanisms that may be responsible for the mediator specific regulation of
macrophage gene expression through the PPAR isoforms, indicating a possible
physiological and potential role for this transcription factor in modulating arterial lipid
metabolism and inflammatory response associated with atherosclerosis
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Keywords
Peroxisome proliferator , Macrophage J774.2 , Receptor (ppar)