Pathophysiological and pharmacological studies on chemokines

本研究旨在通过阐明白介素8(IL-8)和单核细胞趋化激活因子(MCAF/MCP-1)等趋化因子的病理生理作用，开发新型抗炎免疫调节剂。通过这些研究，我们获得了如下结果：#1.与Thestrup-Pedersen博士合作，我们观察到与正常人相比，HIV感染无症状患者B细胞上IL-8受体的表达上调。此外，我们观察到HIV感染患者的B细胞对不同的Th1和Th2细胞因子的IL-8受体表达的反应是不同的。#2.我们与Thestrup-Pedersen博士的团队合作，证明了肝移植后血浆IL-8水平立即升高，可能反映了移植器官的再灌注损伤。#3.与Oppenheim博士的团队合作，我们证明IL-8诱导CXCR2(IL-8受体B型)的磷酸化比NAP-2更强。此外，我们发现强烈的磷酸化导致中性粒细胞对高浓度IL-8的趋化活性降低。#4.我们与Oppenheim博士合作，建立了一种灵敏的CC血细胞因子--嗜酸性粒细胞趋化因子的酶联免疫吸附试验。#5.我们建立了IL-8在中性粒细胞介导的组织损伤中的重要作用，如兔急性呼吸窘迫综合征和脑再灌注损伤模型。此外，我们还揭示了MCAF/MCP-1在抗肾小球基底膜抗血清诱导的新月体肾炎模型中起着至关重要的作用。#6.我们证明了巨细胞病毒在体外诱导IL-8的产生以及IL-8减弱干扰素的抗病毒活性。

This study was performed to develop novel types of anti-inflammatory and immunoregulatory agents through elucidating the pathophysiological roles of chemokines including interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1). Through these studies, we obtained the results as follows.#1.In collaboration with Dr.Thestrup-Pedersen's group, we observed that IL-8 recetor expression on B cells was up-regulated in HIV-infected asymptomatic patients, compared with normal persons. Moreover, we observed that B cells from HIV-infeced patients responded differentially to various Th1 and Th2 cytokines, in terms of IL-8 receptor expression.#2.In collaboration with Dr.Thestrup-Pedersen's group, we demonstrated that plasma IL-8 levels elevated immediately after the liver transplantation, probably reflecting reperfusion injury to transplanted organs.#3.In collaboration with Dr.Oppenheim'sgroup, we demonstrated that IL-8 induced the phosphorylation of CXCR2 (IL-8 receptor type B) more strongly, than NAP-2. Moreover, we revealed the strong phosphorylation resulted in reduced neutrophil chemotactic activity in response to high concentrations of IL-8.#4.In collaboration with Dr.Oppenheim, we established a sensitive enzyme-linked immunosorbent assay for a CC hemokine, eotaxin.#5.We established the essential involvement of IL-8 in neutrophil-mediated tissue injuries, such as acute respiratory distress syndrome and brain reperfusion injury model of rabbit. Moreover, we revealed that MCAF/MCP-1 was crucially involved in anti-glomerular basement membrane antisera-induced crescentic shronic glomerulonephritis model.#6.We demonstrated that cytomegalovirus induced IL-8 production in vitro and that IL-8 attenuated anti-viral activities of interferon.The discussion with Drs.Thestrup-Pedersen and Oppenheim has given us invaluable advice when performing studies #5 and #6.