Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS
Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS
复制标题
DOI：
10.1111/j.1460-9568.2004.03514.x
复制
发表时间：
2004-07-01
影响因子：
3.4
通讯作者：
DeLeo, JA
中科院分区：
文献类型：
--
作者：
Raghavendra, V;Tanga, RY;DeLeo, JA
外周炎症诱导中枢敏感化，其特征在于对机械和热刺激的异常性疼痛和痛觉过敏的发展。最近的证据表明，神经胶质细胞的激活和随后的促炎细胞因子的增加有助于神经损伤或外周炎症后的行为超敏反应的发展。在本研究中，我们研究了大鼠足底注射完全弗氏佐剂（CFA）后，腰髓、脑干和前脑胶质细胞标志物和促炎细胞因子的mRNA和蛋白表达。通过实时逆转录-聚合酶链反应（RT-PCR）研究小胶质细胞标志物（Mac-1，TLR 4和CD 14）的基因表达，结果显示在炎症的所有阶段（急性，亚急性和慢性），其表达显著增加。相反，仅在炎症的亚急性和慢性阶段观察到星形胶质细胞标志物[胶质细胞酸性蛋白（GFAP）和S100 B]的上调。OX-42（CR 3/CD 11b）和GFAP在不同脑区的免疫反应性增加，也分别观察到急性和亚急性炎症阶段后。在mRNA（通过实时RT-PCR）和蛋白水平（通过ELISA）定量促炎性细胞因子（IL-1 β、IL-6和TNF-α）显示在CFA诱导的外周炎症的急性、亚急性和慢性阶段表达增强。这项研究表明，CFA诱导的外周炎症诱导强大的神经胶质细胞活化和促炎细胞因子脊髓和脊髓上。此外，类似于神经损伤诱导的行为超敏反应，小胶质细胞激活先于CFA诱导的外周炎症后的星形胶质细胞激活，支持小胶质细胞在起始阶段和星形胶质细胞在维持超敏反应中的作用。这些发现进一步支持了一个统一的理论，即神经胶质细胞活化和增强的细胞因子表达在中枢神经系统中有一个角色，在引发行为超敏反应。
Peripheral inflammation induces central sensitization characterized by the development of allodynia and hyperalgesia to mechanical and thermal stimuli. Recent evidence suggests that activation of glial cells and a subsequent increase in proinflarnmatory cytokines contribute to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. In the present study, we examined mRNA and protein expression of glial markers and proinflammatory cytokines at the lumbar spinal cord, brainstem and forebrain following intraplantar administration of complete Freunds adjuvant (CFA) in rats. Gene expression studied by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for microglial markers (Mac-1, TLR4 and CD14) showed a significant increase in their expression during all phases (acute, subacute and chronic) of inflammation. Conversely, up-regulation of astroglial markers [glial fibrillary acidic protein (GFAP) and S100B] was observed only at the subacute and chronic phases of inflammation. Increased immunoreactivity for OX-42 (CR3/CD11b) and GFAP at various brain regions was also observed after the acute and subacute phases of the inflammation, respectively. Quantification of proinflarnmatory cytokines (IL-1beta, IL-6 and TNF-alpha) at the mRNA (by real-time RT-PCR) and protein level (by ELISA) revealed enhanced expression during the acute, subacute and chronic phases of CFA-induced peripheral inflammation. This study demonstrates that CFA-induced peripheral inflammation induces robust glial activation and proinflammatory cytokines both spinally and supraspinally. In addition, similar to nerve injury-induced behavioral hypersensitivity microglial activation preceded astrocytic activation following CFA-induced peripheral inflammation, supporting a role of microglia in the initiation phase and astrocytes in maintaining hypersensitivity. These findings further support a unifying theory that glial activation and enhanced cytokine expression at the CNS have a role in eliciting behavioral hypersensitivity.