University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal D-14558, Germany.
University of São Paulo, Institute of Biomedical Sciences, Cancer Metabolism Research Group, 1524-Cidade Universitária, São Paulo 05508-000, Brazil.
Cytokine. 2020 Dec;136:155241. doi: 10.1016/j.cyto.2020.155241. Epub 2020 Aug 13.
Overweight and obesity are accompanied by insulin resistance, impaired intestinal barrier function resulting in increased lipopolysaccharide (LPS) levels, and a low-grade chronic inflammation that results in macrophage activation. Macrophages produce a range of interleukins as well as prostaglandin E (PGE). To cope with insulin resistance, hyperinsulinemia develops. The purpose of the study was to elucidate how LPS, insulin and PGE might interact to modulate the inflammatory response in macrophages. Human macrophages were either derived by differentiation from U937 cells or isolated from blood mononuclear cells. The macrophages were stimulated with LPS, insulin and PGE. Insulin significantly enhanced the LPS-dependent expression of interleukin-1β and interleukin-8 on both the mRNA and protein levels. Additionally, insulin increased the LPS-dependent induction of enzymes involved in the PGE-synthesis and the production of PGE by macrophages. PGE in turn further enhanced the LPS-dependent expression of cytokines via its G-coupled receptors EP2 and EP4, the latter of which appeared to be more relevant. The combination of all three stimuli resulted in an even higher induction than the combination of LPS plus insulin or LPS plus PGE. Thus, the compensatory hyperinsulinemia might directly and indirectly enhance the LPS-dependent cytokine production in obese individuals.
超重和肥胖伴随着胰岛素抵抗，肠道屏障功能受损导致脂多糖（LPS）水平升高，以及导致巨噬细胞活化的低度慢性炎症。巨噬细胞产生一系列白细胞介素和前列腺素 E（PGE）。为了应对胰岛素抵抗，出现高胰岛素血症。本研究旨在阐明 LPS、胰岛素和 PGE 如何相互作用，调节巨噬细胞的炎症反应。人巨噬细胞通过 U937 细胞分化或从血液单核细胞中分离得到。用 LPS、胰岛素和 PGE 刺激巨噬细胞。胰岛素显著增强了 LPS 依赖性人巨噬细胞白细胞介素-1β和白细胞介素-8 的 mRNA 和蛋白水平表达。此外，胰岛素增加了 LPS 依赖性诱导的前列腺素 E 合成酶和 PGE 的产生。PGE 通过其 G 蛋白偶联受体 EP2 和 EP4 进一步增强了 LPS 依赖性细胞因子的表达，后者似乎更为相关。三种刺激物的组合比 LPS 加胰岛素或 LPS 加 PGE 的组合诱导更高。因此，代偿性高胰岛素血症可能直接和间接增强肥胖个体中 LPS 依赖性细胞因子的产生。
