Millward Jason M, Caruso Maria, Campbell Iain L, Gauldie Jack, Owens Trevor
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
J Immunol. 2007 Jun 15;178(12):8175-82. doi: 10.4049/jimmunol.178.12.8175.
Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-gamma, a cytokine not normally expressed in the CNS. To investigate the role of IFN-gamma in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-gamma (AdIFNgamma) to IFN-gamma-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-gamma that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-gamma induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-gammaR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-gamma-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-gamma vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-gamma induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-gamma-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.
中枢神经系统（CNS）炎症发生于多发性硬化症和实验性自身免疫性脑脊髓炎期间，其特征是γ干扰素（IFN-γ）水平升高，γ干扰素是一种通常不在中枢神经系统中表达的细胞因子。为了研究IFN-γ在中枢神经系统中的作用，我们对IFN-γ缺陷（GKO）小鼠进行鞘内注射编码鼠IFN-γ的复制缺陷型腺病毒（AdIFNγ）。该方法导致IFN-γ稳定、长期表达，使用酶联免疫吸附测定（ELISA）和Luminex微球免疫测定法可在脑脊液中检测到。IFN-γ诱导趋化因子CXCL10和CCL5的信使核糖核酸（mRNA）和蛋白质在中枢神经系统中表达，其水平与实验性自身免疫性脑脊髓炎期间所见水平相当。其他趋化因子（CXCL2、CCL2、CCL3）未被诱导。缺乏IFN-γ受体的小鼠无反应，对照病毒载体未诱导趋化因子表达。趋化因子表达主要定位于脑膜和室管膜细胞，在星形胶质细胞和小胶质细胞中也可见到。IFN-γ诱导的趋化因子表达未导致炎症。然而，当对感染IFN-γ载体的小鼠腹腔注射百日咳毒素时，通过流式细胞术检测到中枢神经系统中T淋巴细胞数量急剧增加。中枢神经系统中源自血液的免疫细胞的这种增加单独使用百日咳毒素时不会发生，并且未表现为组织学上可检测到的炎性病理。这些结果表明，IFN-γ诱导一种特征性的胶质细胞趋化因子反应，其本身不足以促进炎症，并且IFN-γ诱导的中枢神经系统化学引诱信号可与外周感染刺激协同作用，驱使T细胞进入中枢神经系统。
