Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
Department of Experimental Medicine, "Sapienza" University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
J Endocrinol Invest. 2022 Jan;45(1):105-114. doi: 10.1007/s40618-021-01621-5. Epub 2021 Jun 25.
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)γ and tumor necrosis factor (TNF)α 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, IFNγ, TNFα, interleukin (IL)-6 and IL-8 by human CD4 + T and DCs, and onto IFNγ/TNFα-dependent signaling in human cardiomyocytes associated with chemokine release.
Cells maintained within an inflammatory-like microenvironment were exposed to RGZ at near therapy dose (5 µM). ELISA quantified cytokine secretion; qPCR measured mRNA expression; Western blot analyzed protein expression and activation; immunofluorescent analysis detected intracellular IFNγ/TNFα-dependent trafficking.
In human CD4 + T cells and DCs, RGZ inhibited CXCL10 release likely with a transcriptional mechanism, and reduced TNFα only in CD4 + T cells. In human cardiomyocytes, RGZ impaired IFNγ/TNFα 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.
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.
C-X-C 基序趋化因子配体 10（CXCL10）从早期阶段就参与了糖尿病和糖尿病心肌病的发展。罗格列酮（RGZ）具有抗炎特性，可针对干扰素（IFN）γ和肿瘤坏死因子（TNF）α作用下分泌 CXCL10 的心肌细胞。心肌细胞重塑、CD4+T 细胞和树突状细胞（DC）显著促成了炎症微环境的形成，并促进了疾病的发展。我们旨在研究 RGZ 对人 CD4+T 和 DC 炎症诱导的 CXCL10、IFNγ、TNFα、白细胞介素（IL）-6 和 IL-8 分泌的影响，以及与趋化因子释放相关的人心肌细胞中 IFNγ/TNFα 依赖性信号转导。
在类似炎症的微环境中维持的细胞暴露于接近治疗剂量的 RGZ（5µM）。ELISA 定量细胞因子分泌；qPCR 测量 mRNA 表达；Western blot 分析蛋白表达和激活；免疫荧光分析检测细胞内 IFNγ/TNFα 依赖性转运。
在人 CD4+T 细胞和 DC 中，RGZ 可能通过转录机制抑制 CXCL10 释放，并仅在 CD4+T 细胞中减少 TNFα。在人心肌细胞中，RGZ 损害了 IFNγ/TNFα 信号转导，阻断了信号转导和转录激活因子 1（Stat1）和核因子-κB（NF-κB）的磷酸化/核易位，与 CXCL10 表达、IL-6 和 IL-8 释放的显著减少相关。
由于 Th1 生物标志物（如 CXCL10、IL-8、IL-6）与经典心血管危险因素的组合似乎可以提高预测 T2D 和冠状动脉事件的准确性，因此未来的研究可能需要进一步研究 RGZ 的抗 Th1 作用。
