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

白介素8(IL-8)是我们1987年在美国国立癌症研究所发现的一种新的白细胞趋化激活因子。从那时起，我们利用抗IL-8的单抗建立了IL-8在兔各种疾病模型中的重要作用，包括肺再灌注损伤、急性皮肤炎和关节关节炎。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。在最近两年的研究中，我们进一步证实IL-8参与了血清型肾炎和PPD诱导的迟发性超敏反应。我们还产生了针对小鼠和人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上的表达。我们还检测了IL-8受体在T淋巴细胞上的表达调节，发现干扰素-γ和肿瘤坏死因子-α处理后，IL-8受体高度上调。另一方面，我们以前发现，NFkB与AP-1或NF-IL 6协同作用，对各种炎症刺激具有反应性，从而激活IL-8基因。在这里，我们发现NFkB是已有的抗炎和免疫抑制剂、糖皮质激素和FK506的最终靶点。这些观察表明，可以针对导致NFkB激活的途径(S)开发新的抗炎药物。为了促进这一途径，我们开发了依赖内毒素的NFkB无细胞激活系统，并鉴定了一种蛋白激酶，它可以结合NFkB的负调控因子IkBA并特异性地将其磷酸化。

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.