Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation
Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation
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DOI：
10.1016/s0006-8993(01)02850-5
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发表时间：
2001-10-12
期刊：
影响因子：
2.9
通讯作者：
Reichlin, S
中科院分区：
文献类型：
--
作者：
Funk, JL;Trout, CR;Reichlin, S
PTHrP 是在内毒素血症期间的实质器官和类风湿性关节炎的滑膜中诱导的肽，最近已显示在未成熟或转化的人星形胶质细胞中表达，但在正常细胞中不表达。这一发现使我们推测 PTHrP 也可能在发炎大脑的反应性星形胶质细胞中被诱导，从而充当中枢神经系统炎症的介质。为了检验这一假设，在大鼠皮质刺伤损伤后检查了 PTHrP 表达，这是反应性神经胶质增生的经典模型。为了确定胶质细胞中的 PTHrP 是否由 TNF-α（已知的脑部炎症介质和周围组织中 PTHrP 诱导的介质）诱导，并确定 PTHrP 是否反过来介导胶质细胞中的炎症变化，还对大鼠星形胶质细胞和富含胶质细胞的混合脑细胞进行了体外研究。与之前正常脑中 PTHrP 表达的报道一致，刺伤后 1 天，神经元是受损皮质中免疫反应性 PTHrP 表达的主要部位。在接下来的 3 天里，伤口边缘的反应性星形胶质细胞和血管周围星形胶质细胞中出现了 PTHrP 和 GFAP（反应性星形胶质细胞标记物）的特异性免疫染色，在最后检查的时间点（第 4 天）达到了最大表达水平。 TNF-α 在体外诱导星形胶质细胞和富含神经胶质的脑细胞中 PTHrP 表达，表明这种促炎肽可能是中枢神经系统炎症中 PTHrP 表达的介质。 PTHrP(1-34) 以与 TNF-α 相加的方式作用，诱导星形胶质细胞表达 IL-6，IL-6 是一种具有神经保护作用的细胞因子。 PTHrP(1-34) 和 PTHrP(1-141) 通过 PTH/PTHrP 受体 cAMP 信号通路抑制星形胶质细胞增殖。这些研究表明，PTHrP 与其在其他非中枢神经系统炎症模型中的调节功能类似，可能是大脑炎症反应的重要介质。 (C) 2001 年爱思唯尔科学 BY。版权所有。
PTHrP, a peptide induced in parenchymal organs during endotoxemia and in the synovium in rheumatoid arthritis, has recently been shown to be expressed in immature or transformed human astrocytes, but not in normal cells. This finding has led us to postulate that PTHrP might also be induced in reactive astrocytes in inflamed brain and, thus, act as a mediator of CNS inflammation. To test this hypothesis, PTHrP expression was examined following cortical stab wound injury in rats, a classical model of reactive gliosis. To determine whether PTHrP was induced in glia by TNF-alpha, a known mediator of inflammation in brain and of PTHrP induction in peripheral tissues, and to determine whether PTHrP, in turn, mediated inflammatory changes in glia, in vitro studies with rat astrocytes and glial-enriched mixed brain cells were also undertaken. Consistent with previous reports of PTHrP expression in normal brain, neurons were the primary site of immunoreactive PTHrP expression in the injured cortex 1 day after stab wound injury. Over the subsequent 3 days, specific immunostaining for PTHrP and for GFAP, a marker of reactive astrocytes, appeared in reactive astrocytes at the wound edge and in perivascular astrocytes, reaching a maximum level of expression at the last time point examined (day 4). TNF-alpha induced PTHrP expression in astrocyte and glial-enriched brain cells in vitro, suggesting that this pro-inflammatory peptide was a possible mediator of PTHrP expression in CNS inflammation. PTHrP(1-34) acted in an additive fashion with TNF-alpha to induced astrocyte expression of IL-6, a cytokine with demonstrated neuroprotective effects. Astrocyte proliferation was inhibited by PTHrP(1-34) and PTHrP(1-141), acting via a PTH/PTHrP receptor cAMP signaling pathway. These studies suggest that PTHrP, analogous to its regulatory functions in other non-CNS models of inflammation, may be an important mediator of the inflammatory response in brain. (C) 2001 Elsevier Science BY. All rights reserved.