Pathophysiological and pharmacological studies on chemokines

趋化因子的病理生理学和药理学研究

• 批准号: 08044263
• 负责人: MATSUSHIMA Kouji
• 金额: $ 6.91万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044263/
• 关键词: Chemokine; interleukin-8; MCAF; MCP-1; neutrophils; monocytes; inflammation; HIV infection; receptor; 糸球体腎炎; 急性呼吸窮迫症候群

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.

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学作用来开发新型抗炎和免疫调节剂。通过这些研究，我们得到了如下结果。#1.与Thestrup-Pedersen博士的团队合作，我们观察到与正常人相比，HIV感染者的无症状患者B细胞上的IL-8受体表达上调。此外，我们观察到 HIV 感染患者的 B 细胞在 IL-8 受体表达方面对各种 Th1 和 Th2 细胞因子的反应存在差异。#2.与 Thestrup-Pedersen 博士的团队合作，我们证明血浆 IL-8 水平在肝移植后立即升高，可能反映了移植器官的再灌注损伤。#3.与 Oppenheim 博士的小组证明，IL-8 比 NAP-2 更强烈地诱导 CXCR2（B 型 IL-8 受体）磷酸化。此外，我们发现强磷酸化导致中性粒细胞对高浓度 IL-8 的趋化活性降低。#4。与 Oppenheim 博士合作，我们建立了一种针对 CC 血因子、嗜酸细胞趋化因子的灵敏酶联免疫吸附测定法。​​#5。我们确定了 IL-8 在中性粒细胞介导的组织损伤中的重要参与，例如 兔急性呼吸窘迫综合征及脑再灌注损伤模型。此外，我们发现 MCAF/MCP-1 在抗肾小球基底膜抗血清诱导的新月体慢性肾小球肾炎模型中发挥着至关重要的作用。#6。我们证明，巨细胞病毒在体外诱导 IL-8 产生，并且 IL-8 减弱了干扰素的抗病毒活性。与 Thestrup-Pedersen 和 Oppenheim 博士的讨论给了我们 在进行研究 #5 和 #6 时提供宝贵的建议。

项目成果

Khadar, K.S.A., Al-Zoghaibi, Al-Ahdal, M.N., F., Murayama, T., Dhalla, M., Mukaida, N., Taha, M., Al-Sedairy, S.T., Siddiqui, Y.M., Kessie, G., and Matsushima, K.: "The alpha-Chemokine, interleukin-8, inhibits the antiviral action of interferon alpha." J.

Khadar, K.S.A.、Al-Zoghaibi、Al-Ahdal, M.N., F.、Murayama, T.、Dhalla, M.、Mukaida, N.、Taha, M.、Al-Sedairy, S.T.、Siddiqui, Y.M.、Kessie, G

Jinquan,T.,et.al.: "Chemotaxis and IL-8 receptor expression in B cells from normal and HIV-infected subjects." J.Immunol.158. 475-484 (1997)

Jinquan,T.,et.al.：“正常和 HIV 感染者 B 细胞中的趋化性和 IL-8 受体表达。”

Murayama, T. et al.: "Human cytimegalovirus induces interleukin-8 production by a human monocytic cell line, THP-1, through acting concurrently on AP-1 and NF-kB binding sites of the interleukin-8 gene." J. Virol.71. 5692-5695 (1997)

Murayama, T. 等人：“人类巨细胞病毒通过同时作用于白细胞介素 8 基因的 AP-1 和 NF-kB 结合位点，诱导人类单核细胞系 THP-1 产生白细胞介素 8。”

Mukaida, N. et al.: "The biological, biochemical and molecular profile of leukocyte chemotactic and activating cytokine, interleukin-8." JAI Pres, Inc., Greenwich,CT,U. S. A., 39 (1997)

Mukaida, N. 等人：“白细胞趋化和激活细胞因子 IL-8 的生物学、生化和分子特征。”

Gesser,B.,et.al.: "IL 8 induces T cell chemotaxiz,suppresses IL 4,and up-regulates IL 8 production by CD4+ Tcells." J.Leukoc.Biol.59. 407-411 (1996)

Gesser,B.,et.al.：“IL 8 诱导 T 细胞趋化，抑制 IL 4，并上调 CD4 T 细胞产生 IL 8。”