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- Open Access
A potential mechanism for anti-inflammatory effects of PPARs
- Andy Clark1
© Current Science Ltd 1999
- Published: 26 November 1999
Atherosclerosis is characterised by chronic inflammation, the presence of activated macrophages and proinflammatory cytokines, including interleukin-6 (IL-6). The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor family of transcription factors, and have been described as antagonists of proinflammatory cytokine synthesis. Ligands of PPARa inhibit IL-6 expression in atherosclerosis, and in isolated IL-1-stimulated aortic smooth muscle cells. The mechanism of action of PPARs is not known. To examine the molecular mechanism by which PPARs inhibit the production of IL-6.
Aortic explants from PPARa -/- mice overexpressed IL-6 protein in response to an liposaccaride (LPS) challenge. The knockout mice were also resistant to the inhibitory effects of a PPARa ligand upon IL-6 mRNA expression. In isolated human aortic smooth muscle cells, a PPARa ligand reduced expression of IL-6 mRNA in response to an IL-1 challenge. The IL-6 promoter contains NF-?B and AP-1 binding sites, and was activated by coexpression of the NF-aB component p65, or the AP-1 component c-jun in transfected COS-1 cells. Either activation was blocked by PPARa coexpression. Reciprocally, activation of an appropriate reporter construct by PPARa was inhibited by p65 or c-jun coexpression. Chimeric transcription factors were used to demonstrate that inhibition occurs at the level of transcriptional activation rather than DNA binding. Direct interactions between PPARa and p65 or c-jun were demonstrated by means of affinity chromatography.
ELISAs and northern blots are used to examine IL-6 protein and mRNA expression in aortic explants of wild type and PPARa, knockout mice and isolated human aortic smooth muscle cells. The mechanism of action of PPARa is examined by means of transient transfection and reporter gene assays in COS-1 cells (a monkey kidney fibroblast line). Protein-protein interactions are assessed by means of affinity chromatography using bacterially-expressed and in vitro translated proteins.
See related report on Huang et al
Nature 1999, 400:378-382.
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