Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages
Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages
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DOI：
10.1210/en.2005-0519
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发表时间：
2006-05-01
期刊：
影响因子：
4.8
通讯作者：
Nadler, JL
中科院分区：
文献类型：
--
作者：
Wen, YS;Gu, JL;Nadler, JL
炎症正在成为糖尿病微血管和大血管并发症的一种重要机制。巨噬细胞在慢性炎症反应中起关键作用，部分是通过产生特定的细胞因子。白细胞介素 - 1β、白细胞介素 - 6、白细胞介素 - 12、白细胞介素 - 18、肿瘤坏死因子α和干扰素 - γ主要由巨噬细胞产生，并且与动脉粥样硬化加速和血管壁功能改变有关。在本研究中，我们评估了高糖（HG）对小鼠腹腔巨噬细胞（MPM）中这些细胞因子基因表达的影响及其机制。HG导致这些细胞因子的mRNA表达增加2倍，其中白细胞介素 - 12以时间依赖（3 - 12小时）和剂量依赖（10、17.5和25 mmol/L）的方式显示出最高的激活（5.4倍）。这种作用是HG特异性的，因为甘露醇和3 - O - 甲基 - 葡萄糖对细胞因子mRNA表达没有影响。HG还增加了MPM中白细胞介素 - 12蛋白的积累。我们还探讨了诱导性和自发性糖尿病对MPM中炎性细胞因子表达的作用。在链脲佐菌素诱导的1型糖尿病小鼠以及2型糖尿病db/db小鼠中，观察到多种炎性细胞因子在MPM中的表达增加，包括白细胞介素 - 12 mRNA增加20倍，这表明体内高血糖会增加细胞因子基因的表达。接下来我们探讨了HG诱导白细胞介素 - 12 mRNA增加的潜在机制。HG增加了MPM中蛋白激酶C、p38丝裂原活化蛋白激酶（p38）、c - Jun末端激酶和抑制性κB激酶的活性。此外，这些信号通路的抑制剂显著降低了HG诱导的MPM中白细胞介素 - 12 mRNA的表达。这些结果为将高血糖和糖尿病与炎症联系起来的一种潜在重要机制提供了证据。
Inflammation is emerging as an important mechanism for microand macrovascular complication of diabetes. The macrophage plays a key role in the chronic inflammatory response in part by generating particular cytokines. IL-1 beta, IL-6, IL12, IL-18, TNF alpha, and interferon-gamma are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3-12 h) and dosedependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin- induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HGincreased the activity of protein kinase C, p38MAPK (p38), c-Jun terminal kinase, and inhibitory-kappa B kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation.