Chun Huang, Hao Wu, Honghai Zhang, Ning Li, Yasong Wu, Chen Dexi
STD/AIDS Research Center, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
Brain Res. 2009 Feb 27;1257:75-88. doi: 10.1016/j.brainres.2008.11.088. Epub 2008 Dec 9.
Neurodegeneration is a characteristic feature of AIDS dementia complex and is commonly associated with neuronal death in the brains of both pediatric and adult patients. Neuronal death associated with AIDS dementia complex can be induced by the HIV-1 protein gp120, but the underlying signal transduction mechanism remains unclear, especially for HIV-1 subtypes commonly seen in China. We have now demonstrated that the human CC ligand 3-like protein 1 (CCL3L1), a member of the CC chemokine family, appears to protect neuronal cultures through its ability to attenuate gp120-induced neuronal death. We found that (i) both pCREB levels and Bcl-2 expression are up-regulated in neuronal culture following treatment with CCL3L1 plus gp120; (ii) CCL3L1 induces cell survival via phosphorylation of CREB by way of the PKA and CaMKI/CaMKIV cell signaling pathways; (iii) transcription of the cell survival gene bcl-2 is induced by pCREB; and (iv) CCL3L1 protects cultured neurons against CCR5-mediated excitotoxicity induced by gp120. Thus, the CCL3L1/bcl-2-regulated anti-apoptotic pathway significantly contributes to reduction of HIV-1/gp120-induced neuronal apoptosis, and therefore, CCL3L1 should be further investigated as a potential chemokine to protect against neuronal injury in gp120-related neuronal toxicity.
神经退行性变是艾滋病痴呆综合征的一个特征性表现，并且在儿科和成年患者大脑中通常与神经元死亡相关。与艾滋病痴呆综合征相关的神经元死亡可由HIV-1蛋白gp120诱导，但潜在的信号转导机制仍不清楚，尤其是在中国常见的HIV-1亚型。我们现已证明，人CC趋化因子配体3样蛋白1（CCL3L1），一种CC趋化因子家族成员，似乎通过减弱gp120诱导的神经元死亡的能力来保护神经元培养物。我们发现：（i）用CCL3L1加gp120处理后，神经元培养物中的pCREB水平和Bcl-2表达均上调；（ii）CCL3L1通过PKA和CaMKI/CaMKIV细胞信号通路使CREB磷酸化从而诱导细胞存活；（iii）细胞存活基因bcl-2的转录由pCREB诱导；（iv）CCL3L1保护培养的神经元免受gp120诱导的CCR5介导的兴奋毒性。因此，CCL3L1/bcl-2调节的抗凋亡途径对减少HIV-1/gp120诱导的神经元凋亡有显著作用，因此，CCL3L1作为一种潜在的趋化因子以预防gp120相关神经元毒性中的神经元损伤应进一步研究。
