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 E2 (PGE2). To cope with insulin resistance, hyperinsulinemia develops. The purpose of the study was to elucidate how LPS, insulin and PGE2 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 PGE2. 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 PGE2-synthesis and the production of PGE2 by macrophages. PGE2 in turn further enhanced the LPS-dependent expression of cytokines via its Gs-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 PGE2. Thus, the compensatory hyperinsulinemia might directly and indirectly enhance the LPS-dependent cytokine production in obese individuals.

中文翻译：

---

胰岛素对人巨噬细胞中 LPS 诱导的细胞因子产生的直接和间接调节

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以及前列腺素 E2 (PGE2)。为了应对胰岛​​素抵抗，会出现高胰岛素血症。该研究的目的是阐明 LPS、胰岛素和 PGE2 如何相互作用以调节巨噬细胞的炎症反应。人类巨噬细胞要么是通过从 U937 细胞分化而来的，要么是从血液单核细胞中分离出来的。巨噬细胞用 LPS、胰岛素和 PGE2 刺激。胰岛素在 mRNA 和蛋白质水平上显着增强了白细胞介素 1β 和白细胞介素 8 的 LPS 依赖性表达。此外，胰岛素增加了参与 PGE2 合成和巨噬细胞产生 PGE2 的酶的 LPS 依赖性诱导。PGE2 反过来通过其 Gs 偶联受体 EP2 和 EP4 进一步增强细胞因子的 LPS 依赖性表达，后者似乎更相关。所有三种刺激的组合导致比 LPS 加胰岛素或 LPS 加 PGE2 的组合更高的诱导。因此，代偿性高胰岛素血症可能直接和间接地增强肥胖个体中 LPS 依赖性细胞因子的产生。所有三种刺激的组合导致比 LPS 加胰岛素或 LPS 加 PGE2 的组合更高的诱导。因此，代偿性高胰岛素血症可能直接和间接地增强肥胖个体中 LPS 依赖性细胞因子的产生。所有三种刺激的组合导致比 LPS 加胰岛素或 LPS 加 PGE2 的组合更高的诱导。因此，代偿性高胰岛素血症可能直接和间接地增强肥胖个体中 LPS 依赖性细胞因子的产生。