High Glucose-Induced Expression of Proinflammatory Cytokine and Chemokine Genes in Monocytic Cells

TLDR

Monocyte activation and adhesion to the endothelium contribute to inflammatory and cardiovascular diseases, and hyperglycemia exacerbates these processes, leading to complications in diabetes. The study aimed to determine how high glucose affects the expression of additional inflammatory genes in THP‑1 monocytes. Researchers performed HG‑induced gene profiling using a cytokine array of 375 known genes in THP‑1 cells. High glucose upregulated 41 inflammatory genes and downregulated 15, including chemokines, cytokines, adhesion molecules, and integrins; RT‑PCR confirmed increased MCP‑1, TNF‑α, β2‑integrin, and IL‑1β expression, and MCP‑1 transcription, protein levels, and monocyte adhesion were elevated and blocked by inhibitors of oxidant stress, PKC, ERK1/2, and p38 MAPK, demonstrating that HG induces diabetes‑related inflammatory mediators through key signaling pathways.

Abstract

Monocyte activation and adhesion to the endothelium play important roles in inflammatory and cardiovascular diseases. These processes are further aggravated by hyperglycemia, leading to cardiovascular complications in diabetes. We have previously shown that high glucose (HG) treatment activates monocytes and induces the expression of tumor necrosis factor (TNF)-α via oxidant stress and nuclear factor-kB transcription factor. To determine the effects of HG on the expression of other inflammatory genes, in the present study, HG-induced gene profiling was performed in THP-1 monocytes using cytokine gene arrays containing 375 known genes. HG treatment upregulated the expression of 41 genes and downregulated 15 genes that included chemokines, cytokines, chemokines receptors, adhesion molecules, and integrins. RT-PCR analysis further confirmed that HG significantly increased the expression of monocyte chemoattractant protein-1 (MCP-1), TNF-α, β2-integrin, interleukin-1β, and others. HG treatment increased transcription of the MCP-1 gene, MCP-1 protein levels, and adhesion of THP-1 cells to endothelial cells. HG-induced MCP-1 mRNA expression and monocyte adhesion were blocked by specific inhibitors of oxidant stress, protein kinase C, ERK1/2, and p38 mitogen-activated protein kinases. These results show for the first time that multiple inflammatory cytokines and chemokines relevant to the pathogenesis of diabetes complications are induced by HG via key signaling pathways.