The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver.
OBJECTIVE
The Peroxisome Proliferator-Activated Receptor (PPAR) alpha belongs to the superfamily of Nuclear Receptors and plays an important role in numerous cellular processes, including lipid metabolism. It is known that PPARalpha also has an anti-inflammatory effect, which is mainly achieved by down-regulating pro-inflammatory genes. The objective of this study was to further characterize the role of PPARalpha in inflammatory gene regulation in liver.


RESULTS
According to Affymetrix micro-array analysis, the expression of various inflammatory genes in liver was decreased by treatment of mice with the synthetic PPARalpha agonist Wy14643 in a PPARalpha-dependent manner. In contrast, expression of Interleukin-1 receptor antagonist (IL-1ra), which was acutely stimulated by LPS treatment, was induced by PPARalpha. Up-regulation of IL-1ra by LPS was lower in PPARalpha -/- mice compared to Wt mice. Transactivation and chromatin immunoprecipitation studies identified IL-1ra as a direct positive target gene of PPARalpha with a functional PPRE present in the promoter. Up-regulation of IL-1ra by PPARalpha was conserved in human HepG2 hepatoma cells and the human monocyte/macrophage THP-1 cell line.


CONCLUSIONS
In addition to down-regulating expression of pro-inflammatory genes, PPARalpha suppresses the inflammatory response by direct up-regulation of genes with anti-inflammatory properties.
Stienstra
Rinke
R
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands.
Mandard
Stéphane
S
Tan
Nguan Soon
NS
Wahli
Walter
W
Trautwein
Christian
C
Richardson
Terrilyn A
TA
Lichtenauer-Kaligis
Elgin
E
Kersten
Sander
S
Müller
Michael
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
D000924:Anticholesteremic Agents; D007004:Hypoglycemic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C006253:pirinixic acid