Grimm M C, Ben-Baruch A, Taub D D, Howard O M, Resau J H, Wang J M, Ali H, Richardson R, Snyderman R, Oppenheim J J
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, Science Applications International Corp. Frederick, Frederick, Maryland 21702, USA.
J Exp Med. 1998 Jul 20;188(2):317-25. doi: 10.1084/jem.188.2.317.
An intact chemotactic response is vital for leukocyte trafficking and host defense. Opiates are known to exert a number of immunomodulating effects in vitro and in vivo, and we sought to determine whether they were capable of inhibiting chemokine-induced directional migration of human leukocytes, and if so, to ascertain the mechanism involved. The endogenous opioid met-enkephalin induced monocyte chemotaxis in a pertussis toxin-sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8-induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1beta-induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by delta and micro but not kappa G protein-coupled opiate receptors. Calcium flux induced by chemokines was unaffected by met-enkephalin pretreatment. Unlike other opiate-induced changes in leukocyte function, the inhibition of chemotaxis was not mediated by nitric oxide. Opiates induced phosphorylation of the chemokine receptors CXCR1 and CXCR2, but neither induced internalization of chemokine receptors nor perturbed chemokine binding. Thus, inhibition of chemokine-induced chemotaxis by opiates is due to heterologous desensitization through phosphorylation of chemokine receptors. This may contribute to the defects in host defense seen with opiate abuse and has important implications for immunomodulation induced by several endogenous neuropeptides which act through G protein-coupled receptors.
完整的趋化反应对于白细胞运输和宿主防御至关重要。已知阿片类药物在体外和体内发挥多种免疫调节作用，我们试图确定它们是否能够抑制趋化因子诱导的人白细胞定向迁移，如果可以，还要确定其中涉及的机制。内源性阿片肽甲硫氨酸脑啡肽以百日咳毒素敏感的方式诱导单核细胞趋化。甲硫氨酸脑啡肽以及吗啡抑制白细胞介素-8诱导的人中性粒细胞趋化以及巨噬细胞炎性蛋白（MIP）-1α、活化调节正常T细胞表达和分泌因子（RANTES）和单核细胞趋化蛋白1诱导的趋化，但不抑制MIP-1β诱导的人单核细胞趋化。这种趋化抑制是由δ和μ而非κG蛋白偶联阿片受体介导的。趋化因子诱导的钙通量不受甲硫氨酸脑啡肽预处理的影响。与阿片类药物诱导的白细胞功能的其他变化不同，趋化抑制不是由一氧化氮介导的。阿片类药物诱导趋化因子受体CXCR1和CXCR2磷酸化，但既不诱导趋化因子受体内化，也不干扰趋化因子结合。因此，阿片类药物对趋化因子诱导的趋化的抑制是由于趋化因子受体磷酸化导致的异源脱敏。这可能导致阿片类药物滥用时宿主防御缺陷，并对几种通过G蛋白偶联受体起作用的内源性神经肽诱导的免疫调节具有重要意义。
