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首页> 外文期刊>Journal of neuroinflammation >Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators
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Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators

机译：人小胶质细胞中胰岛素样生长因子1和2（IGF1，IGF2）的表达：炎症介质的差异调节

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Background Recent studies in experimental animals show that insulin-like growth factor 1 (IGF1) plays a trophic role during development and tissue injury and that microglia are important sources of IGF1. However, little information is available regarding the expression, regulation, and function of IGF1 and related proteins in human brain cells. In the current study, we examined the expression of IGF1 and IGF2 in human microglia in vivo and in vitro. Methods Expression of IGF1 and IGF2 was examined by immunohistochemistry in post-mortem human brain sections derived from HIV+ and HIV? brains. In primary cultures of human fetal microglia, IGF1 and IGF2 mRNA and protein expression was examined by Q-PCR, ELISA, and Western blot analysis. Additionally, the role of IGF1 and IGF2 in neuroprotection was examined in primary human neuronal glial cultures. Results Immunohistochemistry of human brain tissues showed that nonparenchymal cells (vessels and meninges), as well as parenchymal microglia and macrophages were positive for IGF1, in both HIV encephalitis and control brains, while IGF2 was undetectable. Cultured microglia expressed IGF1 mRNA and produced pg/ml levels of IGF1 protein; this was significantly suppressed by proinflammatory mediators, such as lipopolysaccharide (LPS), poly(I:C), and IFNγ. The Th2 cytokines IL-4 and IL-13 had no significant effect, but the cAMP analog (dibutyryl cAMP) significantly increased IGF1 production. In contrast, microglial IGF2 mRNA and protein (determined by Western blot) were upregulated by LPS. IGF1 receptor (IGF1R) immunoreactivity was predominantly expressed by neurons, and both IGF1 and IGF2 significantly protected neurons from cytokine (IL-1/IFNγ) induced death. Conclusions Our study in human brain tissues and cells indicates that microglia are important sources of neurotrophic growth factors IGF1 and IGF2, and that microglial activation phenotypes can influence the growth factor expression. Importantly, our results suggest that chronic neuroinflammation and upregulation of proinflammatory cytokines could lead to neurodegeneration by suppressing the production of microglia-derived neuronal growth factors, such as IGF1.
机译：背景技术最近在实验动物中进行的研究表明，胰岛素样生长因子1（IGF1）在发育和组织损伤中起营养作用，小胶质细胞是IGF1的重要来源。但是，关于IGF1和相关蛋白在人脑细胞中的表达，调控和功能的信息很少。在当前的研究中，我们检查了体内和体外IGF1和IGF2在人小胶质细胞中的表达。方法采用免疫组织化学方法检测HIV +和HIV？致死人脑切片中IGF1和IGF2的表达。大脑。在人胎儿小胶质细胞的原代培养中，通过Q-PCR，ELISA和Western blot分析检查了IGF1和IGF2 mRNA和蛋白的表达。另外，在原代人神经胶质细胞培养物中检查了IGF1和IGF2在神经保护中的作用。结果人脑组织的免疫组织化学显示，在HIV脑炎和对照脑中，非实质细胞（血管和脑膜）以及实质小胶质细胞和巨噬细胞对IGF1呈阳性，而未检测到IGF2。培养的小胶质细胞表达IGF1 mRNA，并产生pg / ml的IGF1蛋白。促炎性介质（例如脂多糖（LPS），聚（I：C）和IFNγ）可显着抑制这种情况。 Th2细胞因子IL-4和IL-13没有明显作用，但cAMP类似物（二丁酰cAMP）显着增加了IGF1的产生。相比之下，LPS会上调小胶质IGF2 mRNA和蛋白质（由Western印迹法测定）。 IGF1受体（IGF1R）的免疫反应主要由神经元表达，而IGF1和IGF2均能显着保护神经元免受细胞因子（IL-1 /IFNγ）诱导的死亡。结论我们在人脑组织和细胞中的研究表明，小胶质细胞是神经营养生长因子IGF1和IGF2的重要来源，并且小胶质细胞活化表型可以影响生长因子的表达。重要的是，我们的研究结果表明，慢性神经炎症和促炎细胞因子的上调可能会通过抑制小胶质细胞衍生的神经元生长因子（例如IGF1）的产生而导致神经退行性变。

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