ICOS/ICOSL upregulation mediates inflammatory response and endothelial dysfunction in type 2 diabetes mellitus

OBJECTIVE: ICOS/ICOSL plays a crucial part in various disease-mediated immune responses. However, the exact role of ICOS/ICOSL in type 2 diabetes mellitus (T2DM) development remains unexplored. This study aims to investigate the role of ICOS/ICOSL in the pathogenesis of T2DM.

MATERIALS AND METHODS: Human peripheral blood T-lymphocytes (CD3) and umbilical vein endothelial cells (HUVECs) were treated with high-glucose (HG) or advanced glycation end products (AGEs). A portion of CD3 cells was co-cultured with HUVECs and treated with different mediums or anti-ICOS mAbs. The ICOS/ICOSL and caspase-3 protein expression was measured by Western blotting. ELISA (enzyme-linked immunosorbent assay), MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and NOx production assays were respectively used to detect cytokines level, cell viability and the production of NOx.

RESULTS: HG and AGEs significantly upregulated ICOS/ICOSL expressions in T cells and HUVECs. T cell contact with HUVECs secreted more IFN-γ, IL-4, and IL-10 compared to non-contact cells, while cytokines from IL-6-, IL-1β-, and CM- (the conditioned medium) treated cells did not differ from the control. A significant increase of IL-8 and IL-6 was found in HUVECs under both contact and non-contact conditions vs. control cells. Similar results were also observed in the comparison between CM1- (T cell condition medium) or CM2- (co-culture condition medium) treated cells and control cells. However, CM1 and CM2 treatment significantly inhibited cell viability and increased caspase-3 and NOx production; blocking ICOS/ICOSL remarkably decreased cytokines secretion, enhanced cell viability and reduced caspase-3 and NOx production.

CONCLUSIONS: HG and AGEs cause T cell inflammatory response and vascular endothelial dysfunction by upregulating ICOS/ICOSL, which may be one of the possible mechanisms of cardiovascular complications development in T2DM patients.

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