Activation of p38 Mitogen-Activated Protein Kinase in Gaucher's Disease
Activation of p38 Mitogen-Activated Protein Kinase in Gaucher's Disease
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DOI：
10.1371/journal.pone.0136633
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发表时间：
2015-08-27
期刊：
影响因子：
3.7
通讯作者：
Hannun, Yusuf A.
中科院分区：
文献类型：
--
作者：
Kitatani, Kazuyuki;Wada, Masayuki;Hannun, Yusuf A.
戈谢病是由酸性β-葡糖苷酶1（GBA 1）缺陷引起的，也被认为是一种炎性疾病。GBA 1裂解葡糖神经酰胺以形成神经酰胺，一种已建立的生物活性脂质，并且GBA 1中的缺陷导致葡糖神经酰胺的异常积累和神经酰胺的形成不足。我们研究了促炎性激酶p38是否在戈谢病中被激活，因为神经酰胺已被提出抑制p38激活。采用三种高雪氏病小鼠模型，并且发现p38在所有高雪氏病小鼠的肺和肝组织中被激活。最有趣的是，神经元病型高雪氏病小鼠，而不是非神经元病型小鼠，在脑组织中显示出显著的p38激活和p38诱导的促炎细胞因子的上调。此外，所有类型的戈谢病小鼠也显示血清IL-6的增加。由于细胞信号传导被认为代表戈谢病中的体内炎性表型，因此在从神经病性戈谢病小鼠建立的成纤维细胞中评估了p38的活化和可能与其相关的促炎细胞因子的形成。在小鼠戈谢病细胞中，与野生型相比，TNF-α处理增强了p38活化和IL-6形成。此外，与健康对应物相比，来自戈谢病患者的人成纤维细胞也显示出p38活化和IL-6形成的增加。这些结果提高了促炎反应如p38激活和IL-6形成在戈谢病中增强的可能性。
Gaucher's disease is caused by defects in acid beta-glucosidase 1 (GBA1) and has been also proposed as an inflammatory disease. GBA1 cleaves glucosylceramide to form ceramide, an established bioactive lipid, and defects in GBA1 lead to aberrant accumulation in glucosylceramide and insufficient formation of ceramide. We investigated if the pro-inflammatory kinase p38 is activated in Gaucher's disease, since ceramide has been proposed to suppress p38 activation. Three Gaucher's disease mouse models were employed, and p38 was found to be activated in lung and liver tissues of all Gaucher's disease mice. Most interestingly, neuronopathic Gaucher's disease type mice, but not non-neuronopathic ones, displayed significant activation of p38 and up-regulation of p38-inducible proinflammatory cytokines in brain tissues. In addition, all type of Gaucher's disease mice also showed increases in serum IL-6. As cellular signalling is believed to represent an in vivo inflammatory phenotype in Gaucher's disease, activation of p38 and possibly its-associated formation of proinflammatory cytokines were assessed in fibroblasts established from neuronopathic Gaucher's disease mice. In mouse Gaucher's disease cells, p38 activation and IL-6 formation by TNF-alpha treatment were enhanced as compared to those of wild type. Furthermore, human fibroblasts from Gaucher's disease patients also displayed increases in p38 activation and IL-6 formation as comparison to healthy counterpart. These results raise the potential that proinflammatory responses such as p38 activation and IL-6 formation are augmented in Gaucher's disease.