Lipid-dependent transcription factors

Activation of retinoic acid receptors was able to prevent influx of macrophages (red cells) and occlusion of artery by matrix in a chronic rejection model.
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Non-steroid nuclear receptors such as retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (e.g. PPARgamma) and liver X receptors (LXRs) are activated by lipid ligands. They have highly significant and long lasting effects on lipid and carbohydrate metabolism and on the immune system. By use of specific synthetic ligands and gene knock out mice we are analyzing the cellular and molecular pathways by which these transcription factors influence chronic inflammation.
In our past experimental approaches we have been able to show that RAR and PPARgamma receptors can inhibit chronic rejection in renal allogenic transplants. The cellular mechanisms are complex and are dependent on the receptor. One common immunosuppressive action is a downregulation of macrophage activity. Macrophages secrete less inflammatory and fibrogenic cytokines; in addition, stimulation of innate immune receptors, namely Toll like Receptors(TLRs) is blocked. Currently the effects of LXRs on fibrosing inflammation are analyzed in several models. LXRs are of major interest as their ligands are synthesized in the microenvironment of inflammation and as their immunosuppressive effects can occur by their modulation of lipid metabolism.


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