Lee Hyunkyoung, Park Chanhee, Cho Ik-Hyun, Kim Hyun Yeong, Jo Eun-Kyeong, Lee Soojin, Kho Hong-Seop, Choi Se-Young, Oh Seog Bae, Park Kyungpyo, Kim Joong Soo, Lee Sung Joong
Program in Molecular and Cellular Neuroscience, Dental Research Institute, Seoul National University, 28 Yeongun-dong, Jongno-gu, Seoul 110-749, Korea.
Glia. 2007 May;55(7):712-22. doi: 10.1002/glia.20493.
Inflammation in the peripheral nervous system (PNS) is one of the characteristics of virus-induced peripheral neuropathy. In this inflammatory response, Schwann cells are actively involved. Previously, toll-like receptor 3 (TLR3) was reported as a receptor for double-stranded RNA (dsRNA) that induces antiviral and inflammatory responses in cells of the innate immune system. In this study, we investigated the expression and putative role of TLR3 in Schwann cells. TLR3 was constitutively expressed in Schwann cells. Stimulation with polyinosinic-polycytidylic acid, a synthetic dsRNA analogue, induced the expression of inducible nitric oxide synthase (iNOS) gene in Schwann cells. Studies on the intracellular signal transduction pathways using iSC, an immortalized Schwann cell line, revealed that dsRNA induces the activation of NF-kappaB, p38, and c-Jun N-terminal kinase (JNK). The activation of NF-kappaB, p38, JNK, and dsRNA-dependent protein kinase is required for dsRNA-mediated iNOS gene expression. However, the activation of PI3 kinase and GSK-3beta inhibited iNOS gene induction, a process mediated by their inhibitory effects on NF-kappaB and p38 activation. dsRNA-induced NO production caused neuronal cell death in cultured dorsal root ganglion. Finally, the introduction of dsRNA into the rat sciatic nerve induced iNOS gene expression and peripheral nerve demyelination in vivo. Taken together, these data suggest that viral RNA may induce inflammatory Schwann cell activation via TLR3 and peripheral nerve damage in the PNS.
外周神经系统（PNS）的炎症是病毒诱导的外周神经病变的特征之一。在这种炎症反应中，施万细胞积极参与其中。此前，Toll样受体3（TLR3）被报道为双链RNA（dsRNA）的受体，可在先天性免疫系统细胞中诱导抗病毒和炎症反应。在本研究中，我们调查了TLR3在施万细胞中的表达及假定作用。TLR3在施万细胞中组成性表达。用合成的dsRNA类似物聚肌苷酸-聚胞苷酸刺激可诱导施万细胞中诱导型一氧化氮合酶（iNOS）基因的表达。使用永生化施万细胞系iSC对细胞内信号转导途径进行的研究表明，dsRNA可诱导核因子κB（NF-κB）、p38和c-Jun氨基末端激酶（JNK）的激活。dsRNA介导的iNOS基因表达需要NF-κB、p38、JNK和dsRNA依赖性蛋白激酶的激活。然而，磷脂酰肌醇-3激酶（PI3激酶）和糖原合成酶激酶-3β（GSK-3β）的激活抑制了iNOS基因的诱导，这一过程是由它们对NF-κB和p38激活的抑制作用介导的。dsRNA诱导的一氧化氮（NO）产生导致培养的背根神经节中的神经元细胞死亡。最后，将dsRNA导入大鼠坐骨神经可在体内诱导iNOS基因表达和周围神经脱髓鞘。综上所述，这些数据表明病毒RNA可能通过TLR3诱导施万细胞的炎症激活以及PNS中的周围神经损伤。
