Morgan T E, Rozovsky I, Sarkar D K, Young-Chan C S, Nichols N R, Laping N J, Finch C E
Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-0191, USA.
Neuroscience. 2000;101(2):313-21. doi: 10.1016/s0306-4522(00)00387-0.
Transforming growth factor-beta1 is a multifunctional peptide with increased expression during Alzheimer's disease and other neurodegenerative conditions which involve inflammatory mechanisms. We examined the autoregulation of transforming growth factor-beta1 and transforming growth factor-beta receptors and the effects of transforming growth factor-beta1 on complement C1q in brains of adult Fischer 344 male rats and in primary glial cultures. Perforant path transection by entorhinal cortex lesioning was used as a model for the hippocampal deafferentation of Alzheimer's disease. In the hippocampus ipsilateral to the lesion, transforming growth factor-beta1 peptide was increased >100-fold; the messenger RNAs encoding transforming growth factor-beta1, transforming growth factor-beta type I and type II receptors were also increased, but to a smaller degree. In this acute lesion paradigm, microglia are the main cell type containing transforming growth factor-beta1, transforming growth factor-beta type I and II receptor messenger RNAs, shown by immunocytochemistry in combination with in situ hybridization. Autoregulation of the transforming growth factor-beta1 system was examined by intraventricular infusion of transforming growth factor-beta1 peptide, which increased hippocampal transforming growth factor-beta1 messenger RNA levels in a dose-dependent fashion. Similarly, transforming growth factor-beta1 increased levels of transforming growth factor-beta1 messenger RNA and transforming growth factor-beta type II receptor messenger RNA (IC(50), 5pM) and increased release of transforming growth factor-beta1 peptide from primary microglia cultures. Interactions of transforming growth factor-beta1 with complement system gene expression are also indicated, because transforming growth factor-beta1 decreased C1qB messenger RNA in the cortex and hippocampus, after intraventricular infusion, and in cultured glia. These indications of autocrine regulation of transforming growth factor-beta1 in the rodent brain support a major role of microglia in neural activities of transforming growth factor-beta1 and give a new link between transforming growth factor-beta1 and the complement system. The auto-induction of the transforming growth factor-beta1 system has implications for transgenic mice that overexpress transforming growth factor-beta1 in brain cells and for its potential role in amyloidogenesis.
转化生长因子-β1是一种多功能肽，在阿尔茨海默病和其他涉及炎症机制的神经退行性疾病中表达增加。我们研究了成年Fischer 344雄性大鼠大脑和原代神经胶质细胞培养物中转化生长因子-β1及其受体的自调节作用，以及转化生长因子-β1对补体C1q的影响。以内嗅皮质损伤造成的穿通通路横断作为阿尔茨海默病海马去传入神经支配的模型。在损伤同侧的海马中，转化生长因子-β1肽增加了100多倍；编码转化生长因子-β1、转化生长因子-βⅠ型和Ⅱ型受体的信使核糖核酸也增加了，但增加程度较小。在这种急性损伤模型中，通过免疫细胞化学结合原位杂交显示，小胶质细胞是含有转化生长因子-β1、转化生长因子-βⅠ型和Ⅱ型受体信使核糖核酸的主要细胞类型。通过脑室内注入转化生长因子-β1肽来研究转化生长因子-β1系统的自调节作用，其以剂量依赖方式增加海马转化生长因子-β1信使核糖核酸水平。同样，转化生长因子-β1增加了转化生长因子-β1信使核糖核酸和转化生长因子-βⅡ型受体信使核糖核酸的水平（半数抑制浓度，5皮摩尔），并增加了原代小胶质细胞培养物中转化生长因子-β1肽的释放。转化生长因子-β1与补体系统基因表达之间的相互作用也有体现，因为脑室内注入后，在皮质和海马以及培养的神经胶质细胞中，转化生长因子-β1降低了C1qB信使核糖核酸水平。啮齿动物大脑中转化生长因子-β1自分泌调节的这些迹象支持了小胶质细胞在转化生长因子-β1神经活动中的主要作用，并在转化生长因子-β1与补体系统之间建立了新的联系。转化生长因子-β1系统的自诱导对在脑细胞中过表达转化生长因子-β1的转基因小鼠及其在淀粉样蛋白生成中的潜在作用具有重要意义。
