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.

这项研究是通过阐明包括白介素8（IL-8）和单核细胞趋化因子和激活因子（MCAF/MCP-1）的趋化因子的病理生理作用来开发新型抗炎和免疫调节剂的新型类型的。通过这些研究，我们获得了如下的结果。＃1。在与Thestup-Pedersen组的合作中，我们观察到与正常人相比，在HIV感染无症状的无症状患者中，B细胞上的IL-8再生表达被上调。此外，我们观察到，在IL-8受体表达方面，来自HIV患者的B细胞对各种Th1和Th2细胞因子的反应差异。 Oppenheim'sgroup博士，我们证明IL-8比NAP-2更强烈地诱导CXCR2（IL-8受体B）的磷酸化。此外，我们揭示了强烈的磷酸化，导致中性粒细胞趋化活性降低，响应于高浓度的IL-8。＃4.与Oppenheim博士的合作，我们建立了一种敏感的酶联免疫吸收分析，用于CC血液的基本含量为INDINSTILISISRISOPISONISERISOD，IL-8-8。兔子急性呼吸窘迫综合征和脑再灌注损伤模型。此外，我们揭示了MCAF/MCP-1与抗胶质细胞基底膜膜抗血素诱导的肌脱鼻肾小球肾炎模型。进行研究＃5和＃6时的宝贵建议。

项目成果

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。”

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

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。”

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。”

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。”