Raung Shue-Ling, Chen Shih-Yun, Liao Su-Lan, Chen Jian-Hong, Chen Chun-Jung
Department of Education and Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
Biochem Biophys Res Commun. 2005 Feb 11;327(2):399-406. doi: 10.1016/j.bbrc.2004.12.034.
The cellular signaling molecules that underlie Japanese encephalitis virus (JEV)-induced inflammation and neurotoxicity are not well understood. We examined whether protein tyrosine kinase (PTK) inhibitors play roles in JEV replication and cytopathic effect in neuron/glia cultures. JEV infection caused significant neuronal injury. PTK inhibitors, genistein, herbimycin A, and PP2, attenuated JEV-induced neurotoxicity but failed to affect JEV replication. Infection of neuron/glia cultures with JEV produced elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). PTK inhibitors suppressed JEV-induced TNF-alpha and IL-1beta production at the transcriptional level. Neutralizing antibodies against TNF-alpha and IL-1beta partially suppressed JEV-induced neurotoxicity. JEV infection modulated tyrosine phosphorylation events within the course of infection. Currently, the nature of the affected phosphorylated proteins was not characterized. Our results suggest that PTKs, especially Src-related PTK, play roles in the production of TNF-alpha and IL-1beta during JEV infection and in the induction of neuronal death in neuron/glia cultures.
目前，对于日本脑炎病毒（JEV）诱导炎症和神经毒性的细胞信号分子还了解甚少。我们研究了蛋白酪氨酸激酶（PTK）抑制剂在神经元/神经胶质细胞培养物中对JEV复制及细胞病变效应的作用。JEV感染导致显著的神经元损伤。PTK抑制剂染料木黄酮、除莠霉素A和PP2可减轻JEV诱导的神经毒性，但未能影响JEV复制。用JEV感染神经元/神经胶质细胞培养物可使肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平升高。PTK抑制剂在转录水平抑制JEV诱导的TNF-α和IL-1β产生。抗TNF-α和IL-1β的中和抗体部分抑制JEV诱导的神经毒性。JEV感染在感染过程中调节酪氨酸磷酸化事件。目前，受影响的磷酸化蛋白的性质尚未明确。我们的结果表明，PTK，尤其是与Src相关的PTK，在JEV感染期间TNF-α和IL-1β的产生以及神经元/神经胶质细胞培养物中神经元死亡的诱导过程中发挥作用。
