Human cell-based anti-inflammatory effects of rosiglitazone

Purpose The C-X-C motif chemokine ligand 10 (CXCL10) participates in diabetes and diabetic cardiomyopathy development from the early stages. Rosiglitazone (RGZ) exhibits anti-inflammatory properties and can target cardiomyocytes secreting CXCL10, under interferon (IFN)gamma and tumor necrosis factor (TNF)alpha challenge. Cardiomyocyte remodeling, CD4 + T cells and dendritic cells (DCs) significantly contribute to the inflammatory milieu underlying and promoting disease development. We aimed to study the effect of RGZ onto inflammation-induced secretion of CXCL10, IFN gamma, TNF alpha, interleukin (IL)-6 and IL-8 by human CD4 + T and DCs, and onto IFN gamma/TNF alpha-dependent signaling in human cardiomyocytes associated with chemokine release. Methods Cells maintained within an inflammatory-like microenvironment were exposed to RGZ at near therapy dose (5 mu M). ELISA quantified cytokine secretion; qPCR measured mRNA expression; Western blot analyzed protein expression and activation; immunofluorescent analysis detected intracellular IFN gamma/TNF alpha-dependent trafficking. Results In human CD4 + T cells and DCs, RGZ inhibited CXCL10 release likely with a transcriptional mechanism, and reduced TNF alpha only in CD4 + T cells. In human cardiomyocytes, RGZ impaired IFN gamma/TNF alpha signal transduction, blocking the phosphorylation/nuclear translocation of signal transducer and activator of transcription 1 (Stat1) and nuclear factor-kB (NF-kB), in association with a significant decrease in CXCL10 expression, IL-6 and IL-8 release. Conclusion As the combination of Th1 biomarkers like CXCL10, IL-8, IL-6 with classical cardiovascular risk factors seems to improve the accuracy in predicting T2D and coronary events, future studies might be desirable to further investigate the anti-Th1 effect of RGZ.

Automated summary

RGZ exerts anti-inflammatory effects by inhibiting CXCL10 release in human CD4 + T cells and DCs, and reducing TNF alpha release in CD4 + T cells. In human cardiomyocytes, RGZ impairs IFN gamma/TNF alpha signaling, leading to decreased CXCL10 expression, IL-6 and IL-8 release. Future studies may further investigate the anti-Th1 effect of RGZ in predicting type 2 diabetes and coronary events.