Establishment of pathophysiological role of interleukin 8 and development of its inhibitors

白细胞介素8病理生理学作用的确立及其抑制剂的开发

• 批准号: 06454218
• 负责人: MATSUSHIMA Kouji
• 金额: $ 4.61万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454218/
• 关键词: Interleukin 8; Pathophysiology; Disease; Antibody; Treatment; Gene; NFkB; Anti-inflammatory drug; インターロイキン 8; 炎症; 組織破壊; 好中球; 受容体; 転写

A novel leukocyte chemotactic and activating factor, interleukin 8 (IL 8) was identified, biochemically purified, and molecularly cloned by us in 1987 at National Cancer Institute. Since then, we have established the essential involvement of IL 8 in various disease models in rabbits, including lung reperfusion injury, acute skin inflammation, and joint arthritis using a monoclonal antibody against IL 8. These works established for the first time an endogenously produced chemotactic factor has an essential role in causing inflammation. During the last two years studies, we further established that IL 8 is involved in serum sickness type glomerulonephritis and PPD-induced delayd type hypersensitivity. We also generated antibodies against murine as well as human IL 8 receptors and studied the expression on various types and maturation stages of leukocytes. We also examined the regulation of the expression of IL 8 receptors on T lymphocytes and found that IL 8 receptors are highly upregulated by treating with interferon gamma and TNF alpha. On the other hand, we previously revealed that NFkB in synergy with AP-1 or NF-IL 6 confers the responsiveness to various inflammatory stimuli to activate IL 8 gene. Here, wehave found that NFkB is an end target of the established anti-inflammatory and immunosuppressants, glucocorticoids and FK506. These observations indicate that novel anti-inflammatory drugs can be developed targeting the pathway (s) leadinf the activation of NFkB.To facilitate the approach, we developed LPS-dependent cell-free activation system of NFkB and identified a protein kinase which binds and specifically phosphorylates a negative regulator of NFkB, IkBa.

1987年，我们在美国国家癌症研究所发现了一种新的白细胞趋化和激活因子-白细胞介素8 (IL 8)，并进行了生化纯化和分子克隆。从那时起，我们已经在兔的各种疾病模型中建立了IL 8的基本参与，包括肺再灌注损伤，急性皮肤炎症和关节关节炎，使用针对IL 8的单克隆抗体。这些工作首次确定了内源性产生的趋化因子在引起炎症中起重要作用。在过去两年的研究中，我们进一步确定了IL 8参与血清病型肾小球肾炎和ppd诱导的延迟型超敏反应。我们还生成了针对小鼠和人IL - 8受体的抗体，并研究了其在不同类型和成熟阶段的白细胞中的表达。我们还研究了IL - 8受体在T淋巴细胞上的表达调节，发现IL - 8受体在干扰素γ和TNF α治疗下高度上调。另一方面，我们之前发现NFkB与AP-1或NF-IL 6协同作用赋予对各种炎症刺激的反应性以激活IL - 8基因。在这里，我们发现NFkB是已建立的抗炎和免疫抑制剂、糖皮质激素和FK506的最终靶点。这些观察结果表明，可以针对导致NFkB激活的途径开发新的抗炎药物。为了促进这种方法，我们开发了依赖于脂多糖的NFkB无细胞激活系统，并鉴定了一种结合并特异性磷酸化NFkB负调节因子IkBa的蛋白激酶。

项目成果

Okamoto,S.-i.: "The interieukin-8 AP-1 and kB-like sites are genetic and tragets of FK506-sensitive pathway accompanied by caicium mobillzation." J.Biol.Chem.269. 8582-8589 (1994)

Okamoto,S.-i.：“interieukin-8 AP-1 和 kB 样位点是遗传性的，是伴随着钙动员的 FK506 敏感途径的目标。”

Kuno,K.: "Acid sphingomyelinase is not essential for the IL 1 and tumor necrosis factor receptor signaling pathway leading to NFkB activation." Int.Immunol.6. 1269-1272 (1994)

Kuno,K.：“酸性鞘磷脂酶对于导致 NFkB 激活的 IL 1 和肿瘤坏死因子受体信号通路不是必需的。”

Ishikawa,Y.: "Establishment of lipopolysaccharide-dependent nuclear factor-kB activation in a cellfree system." J.Biol.Chem.270. 4158-4164 (1995)

Ishikawa,Y.：“在无细胞系统中建立脂多糖依赖性核因子 kB 激活。”

Larsen,C.G.: "The delayed-type hypersensitivity reaction is dependent on IL-8 inhibition of a tuberculin skin reaction by an anti-IL-8 monoclonal antibody." J.Immunol.155. 2151-5157 (1995)

Larsen,C.G.：“迟发型超敏反应依赖于抗 IL-8 单克隆抗体对结核菌素皮肤反应的 IL-8 抑制。”

Xiu,Q.: "Bronchial hyperresponsiveness and airway neutrophil accumulation induced by interleukin-8 and the effect of the thromboxane A2 antagonist S-1452 in guinea-pigs." Clin.Exp.Allergy.25. 51-59 (1995)

Xiu, Q.：“白细胞介素 8 诱导的支气管高反应性和气道中性粒细胞积聚以及血栓素 A2 拮抗剂 S-1452 在豚鼠中的作用。”