Zhou Yan, Ling Eng-Ang, Dheen S Thameem
Department of Anatomy, Molecular Neurobiology Laboratory, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
J Neurochem. 2007 Aug;102(3):667-78. doi: 10.1111/j.1471-4159.2007.04535.x. Epub 2007 Apr 2.
Microglial cells release monocyte chemoattractant protein-1 (MCP-1) which amplifies the inflammation process by promoting recruitment of macrophages and microglia to inflammatory sites in several neurological diseases. In the present study, dexamethasone (Dex), an anti-inflammatory and immunosuppressive drug has been shown to suppress the mRNA and protein expression of MCP-1 in activated microglia resulting in inhibition of microglial migration. This has been further confirmed by the chemotaxis assay which showed that Dex or MCP-1 neutralization with its antibody inhibits the microglial recruitment towards the conditioned medium of lipopolysaccharide (LPS)-treated microglial culture. This study also revealed that the down-regulation of the MCP-1 mRNA expression by Dex in activated microglial cells was mediated via mitogen-activated protein kinase (MAPK) pathways. It has been demonstrated that Dex inhibited the phosphorylation of Jun N-terminal kinase (JNK) and p38 MAP kinases as well as c-jun, the JNK substrate in microglia treated with LPS. The involvement of JNK and p38 MAPK pathways in induction of MCP-1 production in activated microglial cells was confirmed as there was an attenuation of MCP-1 protein release when microglial cells were treated with inhibitors of JNK and p38. In addition, Dex induced the expression of MAP kinase phosphatase-1 (MKP-1), the negative regulator of JNK and p38 MAP kinases in microglial cells exposed to LPS. Blockade of MKP-1 expression by triptolide enhanced the phosphorylation of JNK and p38 MAPK pathways and the mRNA expression of MCP-1 in activated microglial cells treated with Dex. In summary, Dex inhibits the MCP-1 production and subsequent microglial cells migration to the inflammatory site by regulating MKP-1 expression and the p38 and JNK MAPK pathways. This study reveals that the MKP-1 and MCP-1 as novel mediators of biological effects of Dex may help developing better therapeutic strategies for the treatment of patients with neuroinflammatory diseases.
小胶质细胞释放单核细胞趋化蛋白-1（MCP-1），在多种神经疾病中，它通过促进巨噬细胞和小胶质细胞募集至炎症部位来放大炎症过程。在本研究中，抗炎和免疫抑制药物地塞米松（Dex）已被证明可抑制活化小胶质细胞中MCP-1的mRNA和蛋白表达，从而抑制小胶质细胞迁移。趋化性分析进一步证实了这一点，该分析表明Dex或用其抗体中和MCP-1可抑制小胶质细胞向脂多糖（LPS）处理的小胶质细胞培养条件培养基的募集。本研究还表明，Dex在活化小胶质细胞中对MCP-1 mRNA表达的下调是通过丝裂原活化蛋白激酶（MAPK）途径介导的。已证明Dex可抑制LPS处理的小胶质细胞中Jun N端激酶（JNK）和p38 MAP激酶以及JNK底物c-jun的磷酸化。JNK和p38 MAPK途径参与活化小胶质细胞中MCP-1产生的诱导得到了证实，因为用JNK和p38抑制剂处理小胶质细胞时，MCP-1蛋白释放减少。此外，Dex诱导了MAP激酶磷酸酶-1（MKP-1）的表达，MKP-1是暴露于LPS的小胶质细胞中JNK和p38 MAP激酶的负调节因子。雷公藤内酯醇阻断MKP-1表达增强了活化小胶质细胞经Dex处理后的JNK和p38 MAPK途径的磷酸化以及MCP-1的mRNA表达。总之，Dex通过调节MKP-1表达以及p38和JNK MAPK途径来抑制MCP-1产生及随后小胶质细胞向炎症部位的迁移。本研究表明，MKP-1和MCP-1作为Dex生物学效应的新型介质，可能有助于开发更好的治疗策略来治疗神经炎症性疾病患者。
