Peroxisome proliferator-activated receptor gamma agonist troglitazone inhibits high mobility group box 1 expression in endothelial cells via suppressing transcriptional activity of nuclear factor kappaB and activator protein 1.
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Gao M, Hu Z, Zheng Y, Zeng Y, Shen X, Zhong D, He F
Peroxisome proliferator-activated receptor gamma agonist troglitazone inhibits high mobility group box 1 expression in endothelial cells via suppressing transcriptional activity of nuclear factor kappaB and activator protein 1.
Shock. 2011 Sep;36(3):228-34. doi: 10.1097/SHK.0b013e318225b29a.
- PubMed ID
- 21617575 [ View in PubMed]
- Abstract
High mobility group box 1 (HMGB1), a delayed mediator of proinflammatory cytokines, could initiate and amplify inflammatory responses to infection, injury, and other inflammatory stimuli, and it has emerged as a potential therapeutic target for inflammatory diseases. The overexpression of HMGB1 in endothelial cells has been proved to contribute to the development of these diseases. Because many proinflammatory cytokines expression were suppressed by thiazolidinediones (TZDs), agonists for nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), whether TZDs can inhibit HMGB1 expression and function is of great interest, however, it remains unknown. Herein, we provide evidence that PPARgamma agonist troglitazone, a member of the TZD class, modulates HMGB1 expression in the endothelial cell line EA.hy926 and propose a potential mechanism for that. Results from polymerase chain reaction experiments revealed that PPARgamma is expressed in EA.hy926 cells, and it can be activated by troglitazone. Troglitazone inhibited the basal and LPS-stimulated HMGB1 expression at the mRNA level and protein level. A luciferase reporter assay showed that troglitazone inhibited not only the transcriptional activation of the HMGB1 promoter but also activities of heterologous promoters driven by nuclear factor kappaB (NF-kappaB) or activator protein 1 (AP-1) response elements. Altogether, these data suggest that NF-kappaB and AP-1 may participate in the inhibitory effect on HMGB1 transcription induced by troglitazone. Activation of PPARgamma by troglitazone is effective for HMGB1 inhibition via suppressing NF-kappaB and AP-1 transcriptional activity in endothelial cells, which provides a new potential strategy to suppress excessive HMGB1 in inflammatory diseases.