Human cell-based anti-inflammatory effects of rosiglitazone

• Published in: Journal of endocrinological investigation 2022, Vol.45 (1), p.105-114
• Main Authors: Sottili, M., Filardi, T., Cantini, G., Cosmi, L., Morano, S., Luconi, M., Lenzi, A., Crescioli, C.
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - pharmacology; Cardiomyocytes; Cardiomyopathy; Cardiovascular diseases; CD4 antigen; Cells, Cultured; Chemokines; CXCL10 protein; Dendritic cells; Developmental stages; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetic Cardiomyopathies - immunology; Diabetic Cardiomyopathies - metabolism; Endocrinology; Enzyme-linked immunosorbent assay; Gene expression; Humans; Hypoglycemic Agents - pharmacology; Inflammation; Inflammation - metabolism; Interferon-gamma - metabolism; Interleukin 6; Interleukin 8; Interleukin-8 - metabolism; Internal Medicine; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Metabolic Diseases; Microenvironments; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; NF-kappa B - metabolism; NF-κB protein; Nuclear transport; Original Article; Phosphorylation; Prognosis; Risk factors; Rosiglitazone; Rosiglitazone - pharmacology; Signal transduction; Stat1 protein; T-Lymphocytes, Helper-Inducer - immunology; Thiazolidinediones - pharmacology; Transcription; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1720-8386; 0391-4097; 1720-8386
• DOI: 10.1007/s40618-021-01621-5

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)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. Methods 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. Results 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. 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.