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。我们在此研究了阿片肽、内啡肽和脑，以及催乳素在电针局部病变发展中的作用。通过RT-PCR法和放射性同位素结合实验，我们发现了阿片受体μ和δ链在RA滑膜细胞系上的表达。在RA滑膜细胞系培养中加入阿片肽后，细胞增殖受到抑制，炎性细胞因子IL-1、肿瘤坏死因子-α、IL-6和IL-r8的产生减少。这种作用是通过抑制cAMP信号通路实现的，而cAMP信号通路还能干扰另一种神经肽生长抑素和一种特异性的rp-cAMP。由于免疫组织化学研究显示，cAMP反应元件(CREB)在RA滑膜中大量表达，cAMP信号通路可能参与了RA病变滑膜细胞的异常激活状态。因此，神经肽或其衍生物可能是治疗类风湿关节炎的药物。调节神经肽生产的药物可能是另一种选择。在本研究中，我们还发现催乳素通过JAK2-STAT5通路刺激RA滑膜细胞功能，提示该通路是RA治疗的替代药理靶点。综上所述，我们的研究为基于神经-内分泌-免疫轴的RA新药开发提供了重要线索。

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.