Park Chanhee, Lee Soojin, Cho Ik-Hyun, Lee Hyun Kyoung, Kim Donghoon, Choi Se-Young, Oh Seog Bae, Park Kyungpyo, Kim Joong Soo, Lee Sung Joong
Program in Cellular and Molecular Neuroscience and Department of Oral Physiology, College of Dentistry,Seoul National University, Seoul, South Korea.
Glia. 2006 Feb;53(3):248-56. doi: 10.1002/glia.20278.
Viral infection is one of the leading causes of brain encephalitis and meningitis. Recently, it was reported that Toll-like receptor-3 (TLR3) induces a double-stranded RNA (dsRNA)-mediated inflammatory signal in the cells of the innate immune system, and studies suggested that dsRNA may induce inflammation in the central nervous system (CNS) by activating the CNS-resident glial cells. To explore further the connection between dsRNA and inflammation in the CNS, we have studied the effects of dsRNA stimulation in astrocytes. Our results show that the injection of polyinosinic-polycytidylic acid (poly(I:C)), a synthetic dsRNA, into the striatum of the mouse brain induces the activation of astrocytes and the expression of TNF-alpha, IFN-beta, and IP-10. Stimulation with poly(I:C) also induces the expression of these proinflammatory genes in primary astrocytes and in CRT-MG, a human astrocyte cell line. Furthermore, our studies on the intracellular signaling pathways reveal that poly(I:C) stimulation activates IkappaB kinase (IKK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in CRT-MG. Pharmacological inhibitors of nuclear factor-kappaB (NF-kappaB), JNK, ERK, glycogen synthase kinase-3beta (GSK-3beta), and dsRNA-activated protein kinase (PKR) inhibit the expression of IL-8 and IP-10 in astrocytes, indicating that the activation of these signaling molecules is required for the TLR3-mediated chemokine gene induction. Interestingly, the inhibition of PI3 kinase suppressed the expression of IP-10, but upregulated the expression of IL-8, suggesting differential roles for PI3 kinase, depending on the target genes. These data suggest that the TLR3 expressed on astrocytes may initiate an inflammatory response upon viral infection in the CNS.
病毒感染是脑脑炎和脑膜炎的主要病因之一。最近有报道称，Toll样受体3（TLR3）在先天性免疫系统细胞中诱导双链RNA（dsRNA）介导的炎症信号，并且研究表明dsRNA可能通过激活中枢神经系统（CNS）中驻留的神经胶质细胞在中枢神经系统中诱导炎症。为了进一步探索dsRNA与中枢神经系统炎症之间的联系，我们研究了dsRNA刺激对星形胶质细胞的影响。我们的结果表明，将合成的dsRNA聚肌苷酸-聚胞苷酸（poly(I:C)）注射到小鼠脑纹状体中会诱导星形胶质细胞的激活以及肿瘤坏死因子-α（TNF-α）、干扰素-β（IFN-β）和干扰素诱导蛋白10（IP-10）的表达。用poly(I:C)刺激也会在原代星形胶质细胞和人星形胶质细胞系CRT-MG中诱导这些促炎基因的表达。此外，我们对细胞内信号通路的研究表明，poly(I:C)刺激会激活CRT-MG中的IκB激酶（IKK）、细胞外信号调节激酶（ERK）和c-Jun氨基末端激酶（JNK）。核因子-κB（NF-κB）、JNK、ERK、糖原合酶激酶-3β（GSK-3β）和dsRNA激活蛋白激酶（PKR）的药理抑制剂会抑制星形胶质细胞中白细胞介素-8（IL-8）和IP-10的表达，表明这些信号分子的激活是TLR3介导的趋化因子基因诱导所必需的。有趣的是，抑制磷脂酰肌醇-３激酶（PI3激酶）会抑制IP-10的表达，但会上调IL-8的表达，这表明PI3激酶根据靶基因发挥不同作用。这些数据表明，星形胶质细胞上表达的TLR3可能在中枢神经系统病毒感染时引发炎症反应。
