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PPARγ stabilizes HO-1 mRNA in monocytes/macrophages which affects IFN-β expression
Andreas von Knethen1, Holger Neb, Virginie Morbitzer
1Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Theodor-Stern-Kai 7, Germany. v_knethen@zbc.kgu.de
Free Radical Biology & Medicine
|May 17, 2011
Summary
Peroxisome proliferator-activated receptor gamma (PPARγ) stabilizes heme oxygenase-1 (HO-1) mRNA, enhancing interferon-beta (IFN-β) expression in macrophages. This discovery reveals a new role for PPARγ in regulating inflammatory responses.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- NADPH oxidase activation in macrophages triggers reactive oxygen species (ROS) production.
- This activation leads to peroxisome proliferator-activated receptor gamma (PPARγ) activation, heme oxygenase-1 (HO-1) induction, and interferon-beta (IFN-β) expression.
Purpose of the Study:
- To investigate the role of PPARγ in regulating NADPH oxidase-dependent IFN-β expression in macrophages.
- To elucidate the underlying molecular mechanisms, specifically focusing on HO-1 mRNA stability.
Main Methods:
- Utilized RAW264.7 cell lines and primary peritoneal macrophages (PM) from wild-type and PPARγ-deficient mice.
- Employed dominant-negative PPARγ mutants and HO-1 3'-UTR reporter constructs.
- Assessed HO-1 mRNA stability using in vitro and in vivo methods after NADPH oxidase activation.
Main Results:
- NADPH oxidase activation induced PPARγ, HO-1, and IFN-β in wild-type macrophages.
- IFN-β expression was attenuated in macrophages with dominant-negative PPARγ or lacking PPARγ.
- PPARγ deficiency led to decreased HO-1 mRNA stability and reduced IFN-β expression.
- PPARγ activation by rosiglitazone upregulated HO-1 3'-UTR reporter activity, dependent on AU-rich elements.
Conclusions:
- PPARγ plays a crucial role in stabilizing HO-1 mRNA in macrophages.
- This stabilization mechanism contributes to the expression of the HO-1 target gene, IFN-β.
- Identified a novel function of PPARγ in regulating inflammatory gene expression via mRNA stability.
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