Abstract：
The production of superoxide anions and other reactive oxygen species (ROS) by neutrophils is necessary for host defense against microbes. However, excessive ROS production can induce cell damage that participates in the inflammatory response. Superoxide anions are produced by the phagocyte NADPH oxidase, a multicomponent enzyme system consisting of two transmembrane proteins (gp91phox/NOX2 and p22phox) and four soluble cytosolic proteins (p40phox, p47phox, p67phox and the small G proteins Rac1/2). Stimulation of neutrophils by various agonists, such as the bacterial peptide formyl-Met-Leu-Phe (fMLF), induces NADPH oxidase activation and superoxide production, a process that is enhanced by the pro-inflammatory cytokines such as GM-CSF. The pathways involved in this GM-CSF-induced up-regulation or priming are not fully understood. Here we show that GM-CSF induces the activation of the prolyl cis/trans isomerase Pin1 in human neutrophils. Juglone and PiB, two selective Pin1 inhibitors, were able to block GM-CSF-induced priming of ROS production by human neutrophils. Interestingly, GM-CSF induced Pin1 binding to phosphorylated p47phox at Ser345. Neutrophils isolated from synovial fluid of patients with rheumatoid arthritis are known to be primed. Here we show that Pin1 activity was also increased in these neutrophils and that Pin1 inhibitors effectively inhibited ROS hyperproduction by the same cells. These results suggest that the prolyl cis/trans isomerase Pin1 may control GM-CSF-induced priming of ROS production by neutrophils and priming of neutrophils in synovial fluid of rheumatoid arthritis patients. Pharmacological targeting of Pin1 may be a valuable approach to the treatment of inflammation.
摘要：
嗜中性粒细胞产生超氧化物阴离子和其他活性氧（ROS）对于宿主防御微生物是必需的。然而,过量的ROS产生可以诱导参与炎症反应的细胞损伤。超氧阴离子由吞噬细胞NADPH氧化酶产生，由两种跨膜蛋白（gp91phox/NOX2和p22phox）和四种可溶性细胞溶质蛋白（p40phox，p47phox,p67phox和小G蛋白Rac1/2）。各种激动剂刺激嗜中性粒细胞，例如细菌肽甲酰-Met-Leu-Phe（fMLF），诱导NADPH氧化酶活化和超氧化物产生，通过促炎细胞因子如GM-CSF增强的过程。尚未完全了解这种GM-CSF诱导的上调或引发的途径。在这里，我们显示GM-CSF诱导人嗜中性粒细胞中脯氨酸顺式/反式异构酶Pin1的激活。Juglone和PiB,两种选择性Pin1抑制剂，能够阻断GM-CSF诱导的人嗜中性粒细胞产生ROS的引发。有趣的是,GM-CSF诱导Pin1在Ser345处与磷酸化的p47phox结合。已知从类风湿性关节炎患者的滑液中分离出的嗜中性粒细胞被引发。在这里，我们表明Pin1活性在这些中性粒细胞中也增加，并且Pin1抑制剂有效地抑制了相同细胞的ROS过度产生。这些结果表明，脯氨酸顺式/反式异构酶Pin1可以控制GM-CSF诱导的嗜中性粒细胞产生ROS的引发和类风湿关节炎患者滑液中嗜中性粒细胞的引发。Pin1的药理靶向可能是治疗炎症的一种有价值的方法。
