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首页> 外文期刊>Cytokine >Synergistic induction of CXCL10 by interferon-gamma and lymphotoxin-alpha in astrocytes: Possible role in cerebral malaria
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Synergistic induction of CXCL10 by interferon-gamma and lymphotoxin-alpha in astrocytes: Possible role in cerebral malaria

机译：星形胶质细胞中干扰素-γ和淋巴毒素-α协同诱导CXCL10：在脑疟疾中的可能作用

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Cerebral malaria (CM) has a high mortality rate and incidence of neurological sequelae in survivors. Hypoxia and cytokine expression in the brain are two mechanisms thought to contribute to the pathogenesis of CM. The cytokines interferon (IFN)-gamma and lymphotoxin (LT)-alpha and the chemokine CXCL10 are essential for the development of CM in a mouse model. Furthermore, serum IFN-gamma protein levels are higher in human CM than in controls, and CXCL10 is elevated in both serum and cerebrospinal fluid in Ghanaian paediatric CM cases. Astrocytes actively participate in CNS pathologies, becoming activated in response to various stimuli including cytokines. Astrocyte activation also occurs in murine and human CM. We here determined the responsiveness of mouse and human astrocytes to MN-7 and LT-alpha, with the aim of further elucidating the role of astrocytes in CM pathogenesis. Initially we confirmed that Ifn-gamma and Cxcl10 are expressed in the brain in murine CM, and that the increased Cxcl10 expression is IFN-gamma-dependant. IFN-gamma induced CXCL10 production in human and murine astrocytes in vitro. The degree of induction was increased synergistically in the presence of LT-alpha IFN-gamma induced the expression of receptors for LT-alpha, while LT-alpha increased the expression of the receptor for IFN-gamma, in the astrocytes. This cross-induction may explain the synergistic effect of the two cytokines on CXCL10 production. Expression of these receptors also was upregulated in the brain in murine CM. The results suggest that astrocytes contribute to CM pathogenesis by producing CXCL10 in response to IFN-gamma and LT-alpha. (C) 2015 Elsevier Ltd. All rights reserved.
机译：脑性疟疾（CM）的死亡率高，幸存者有神经系统后遗症。大脑中的缺氧和细胞因子表达是导致CM发病的两种机制。细胞因子干扰素（IFN）-γ和淋巴毒素（LT）-α和趋化因子CXCL10对于小鼠模型中CM的发育至关重要。此外，在加纳的小儿CM病例中，人CM中的血清IFN-γ蛋白水平高于对照组，并且血清和脑脊液中CXCL10均升高。星形胶质细胞积极参与中枢神经系统病理，响应包括细胞因子在内的各种刺激而被激活。星形胶质细胞激活也发生在鼠和人CM中。我们在这里确定了小鼠和人类星形胶质细胞对MN-7和LT-alpha的反应性，目的是进一步阐明星形胶质细胞在CM发病机理中的作用。最初，我们确认Ifn-γ和Cxcl10在鼠CM的大脑中表达，并且增加的Cxcl10表达是IFN-γ依赖性的。 IFN-γ在体外诱导人和鼠星形胶质细胞中CXCL10的产生。在星形胶质细胞中，在存在LT-α的情况下，诱导程度协同增加。IFN-γ诱导LT-α受体的表达，而LT-α则增加IFN-γ受体的表达。这种交叉诱导可能解释了两种细胞因子对CXCL10产生的协同作用。这些受体的表达在鼠CM的大脑中也被上调。结果表明，星形胶质细胞通过响应IFN-γ和LT-α产生CXCL10来促进CM发病。 （C）2015 Elsevier Ltd.保留所有权利。

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