Development of novel therapeutic strategies for rheumatoid arthritis based on the neuro - endocrine-immune axis

神经-内分泌-免疫轴参与类风湿关节炎（EA）的病理生理过程。我们在此研究阿片肽、内啡肽、脑磷脂和催乳素在EA局部病变发展中的作用。我们用RT-PCR技术和放射性同位素结合试验检测了类风湿关节炎滑膜细胞系阿片受体μ链和δ链的表达。向RA滑膜细胞系培养物中引入阿片肽导致增殖抑制和炎性细胞因子如IL-1、TNF-α、IL-6和ILr 8的产生减少。这种作用是通过抑制环AMP信号通路介导的，这也被证明是干扰另一种神经肽，生长抑素以及一个特定的，RP-cAMP。环AMP信号通路可能涉及在RA病变的滑膜细胞的异常激活状态，因为免疫组化研究显示，在RA滑膜中的环AMP反应元件（CREB）的表达丰富。因此，神经肽或其衍生物可能是治疗RA的药物。调节神经肽产生的药物可能是另一种选择。本研究还发现催乳素通过JAK 2-STAT 5通路刺激RA滑膜细胞功能，提示该通路是RA治疗的另一个药理学靶点，为从神经-内分泌-免疫轴角度开发治疗RA的新药提供了重要线索。

Neuro-endocrine-immune axis is implicated in the pathophysiology of rheumatoid arthritis (EA). We here investigated roles of opioid peptides, endrophin and encephalin, and prolactin in the development of local lesions of EA. We revealed expression of opioid receptor μ and δ chains on RA synovial cell lines hy RT-PCR techniques and biding assay using radioisotopes. Introduction of opioid peptides into the RA synovial cell line culture resulted in suppressed proliferation and reduced production of inflammatory cytokines such as IL-1, TNF-α, IL-6, and ILr8. The effects were mediated by inhibition of the cyclic AMP signaling pathway, which was also shown to interfered with another neuropeptide, somatostatin as well as a specific, Rp-cAMP The cyclic AMP signaling pathway may be implicated in abnormal activation states of synovial cells in RA lesions, because immunohistochemical study showed abundant expression of cyclic AMP responsive element (CREB) in RA synovium. Therefore, the neuropeptides or their derivatives are possible therapeutic agents for RA. Agents, which modulate the production of the neuropetides, may be another options. In this study, we also found that prolactin stimulated RA synovial cell functions through the JAK2-STAT5 pathway, suggesting that the pathway is an alternative pharmacological target for RA therapy.Collectively, our current study provides important clues to develop novel drugs for RA on the basis of neuro-endocrine-immune axis.