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

白细胞介素8（IL 8）是我们于1987年在美国国家癌症研究所鉴定、纯化和克隆的一种新的白细胞趋化和活化因子。从那时起，我们使用抗IL 8的单克隆抗体确定了IL 8在兔各种疾病模型中的重要作用，包括肺再灌注损伤、急性皮肤炎症和关节炎。这些工作首次建立了内源性产生的趋化因子在引起炎症中具有重要作用。在近两年的研究中，我们进一步证实IL 8参与血清病型肾小球肾炎和PPD诱导的迟发型超敏反应。我们还产生了针对鼠以及人IL 8受体的抗体，并研究了在各种类型和成熟阶段的白细胞上的表达。我们还研究了T淋巴细胞上IL 8受体表达的调节，发现IL 8受体通过干扰素γ和TNF α治疗而高度上调。另一方面，我们先前揭示了NF κ B与AP-1或NF-IL 6协同作用赋予对各种炎症刺激的响应性以激活IL 8基因。我们发现NF κ B是抗炎和免疫抑制剂、糖皮质激素和FK 506的最终靶点。这些观察结果表明，可以开发新的抗炎药物靶向途径导致NF κ B的激活。为了促进该方法，我们开发了LPS依赖的NF κ B无细胞激活系统，并鉴定了一种蛋白激酶，其结合并特异性磷酸化NF κ B的负调节因子IkBa。

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.