Lee Hyunkyoung, Park Kyungpyo, Kim Joong Soo, Lee Sung Joong
Program in Molecular and Cellular Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, Korea.
J Neurosci Res. 2009 Jan;87(1):171-8. doi: 10.1002/jnr.21820.
We have previously reported that polyinosinic-polycytidylic acids [poly(I:C)], a synthetic toll-like receptor 3 (TLR3) agonist, induce Schwann cell activation, which exerts neurotoxic effects on sensory neurons. In this study, we investigated the effects of vasoactive intestinal peptide (VIP), a neuropeptide implicated in nerve regeneration, on TLR3-induced Schwann cell activation. VIP receptors VPAC1 and VPAC2 were constitutively expressed in rat Schwann cells. VIP pretreatment inhibited TLR3-induced inducible nitric oxide synthase (iNOS) gene expression and NO production in Schwann cells. Studies on the intracellular signal transduction pathways indicate that the VIP effect is mediated by protein kinase A activation. VIP also inhibited the poly(I:C)-induced p38 activation that is responsible for the iNOS gene expression in Schwann cells. Finally, VIP inhibited dorsal rooyt ganglion neuronal cell death caused by NO produced in activated Schwann cells. Taken together, our data suggest that VIP exerts a neuroprotective effect by inhibiting neurotoxic Schwann cell activation.
我们之前报道过，多聚肌苷酸-多聚胞苷酸[聚（I:C）]，一种合成的Toll样受体3（TLR3）激动剂，可诱导雪旺细胞活化，对感觉神经元产生神经毒性作用。在本研究中，我们研究了血管活性肠肽（VIP），一种与神经再生有关的神经肽，对TLR3诱导的雪旺细胞活化的影响。VIP受体VPAC1和VPAC2在大鼠雪旺细胞中组成性表达。VIP预处理可抑制TLR3诱导的雪旺细胞中诱导型一氧化氮合酶（iNOS）基因表达和NO产生。对细胞内信号转导途径的研究表明，VIP的作用是由蛋白激酶A激活介导的。VIP还抑制了聚（I:C）诱导的p38活化，而p38活化负责雪旺细胞中iNOS基因的表达。最后，VIP抑制了由活化雪旺细胞产生的NO引起的背根神经节神经元细胞死亡。综上所述，我们的数据表明，VIP通过抑制具有神经毒性的雪旺细胞活化发挥神经保护作用。
