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The basic research for the therapy of Gram-negative bacterial sepsis by LPS-receptors fusion protein

LPS-受体融合蛋白治疗革兰氏阴性细菌性脓毒症的基础研究

基本信息

批准号：
16591807
负责人：
KARIMA Risuke
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

LPS plays a pivotaland initiative role in the development of pathophysiological response of sepsis in gram-negative bacterial infection. It has been revealed that two distinct receptors, CD14 and toll-like receptor 4 (TLR4), are involved in the recognition of LPS stimulation by cells. For the purpose of developing a novel therapy in the early phase of gram-negative bacterial sepsis, the inhibitory effect of recombinant CD14-TLR4-Fc fusion protein against cell stimulation by LPS, comparing the effect of recombinant CD14-Fc fusion protein on the LPS-induced interleukin-8 (IL-8) production by U373 cell line and human peripheral blood mononuclear cells (PBMC). As a result, while CD14-Fc only partially suppressed LPS-induced IL-8 production by cells, CD14-TLR4-Fc significantly inhibited IL-8 production by cells in response to 10ng/ml-1000ng/ml LPS. Especially, the administration of 5 μg/ml of CD14-TLR4-Fc almost completely blocked LPS-induced IL-8 production both in U373 and in human PBMC. The reason why CD14-TLR4-Fc strongly inhibited LPS stimulation may be that LPS cannot associated with TLR4 in the cell surface because of the incorporation with the TLR4 region of the CD14-TLR4-Fc after trapping by this fusion protein. In contrast, LPS trapped by CD14-Fc may still remain the activity of stimulating TLR4 in the cell surface, resulting in the only partial suppression of LPS-induced IL-8 production by cells. The results of this study demonstrate the strong blocking effect of recombinant CD14-TLR4-Fc fusion protein against LPS-induced inflammatory response, indicating the potential possibility for the development of the novel drug for the suppression of excessive inflammatory response in sepsis by gram-negative bacterial infection.

LPS在革兰阴性菌感染脓毒症病理生理反应的发生发展中起着重要的主动作用。已经揭示了两种不同的受体，CD14和Toll样受体4（TLR4），参与细胞对LPS刺激的识别。为探索革兰氏阴性菌脓毒症早期治疗的新方法，本研究比较了重组CD14-TLR4-Fc融合蛋白对LPS诱导的U373细胞和人外周血单个核细胞（PBMC）产生白细胞介素-8（IL-8）的影响。结果，虽然CD14-Fc仅部分抑制LPS诱导的细胞产生IL-8，但CD14-TLR4-Fc显著抑制细胞响应10ng/ml-1000ng/ml LPS产生IL-8。特别地，施用5 μ g/ml的CD14-TLR4-Fc几乎完全阻断U373和人PBMC中LPS诱导的IL-8产生。CD14-TLR4-Fc强烈抑制LPS刺激的原因可能是LPS不能与细胞表面的TLR4结合，因为在被该融合蛋白捕获后，LPS与CD14-TLR4-Fc的TLR4区域结合。相反，被CD14-Fc捕获的LPS可能仍然保持刺激细胞表面TLR4的活性，导致仅部分抑制LPS诱导的细胞产生IL-8。本研究结果表明重组CD14-TLR4-Fc融合蛋白对LPS诱导的炎症反应具有较强的阻断作用，表明开发新型药物抑制革兰氏阴性菌感染脓毒症过度炎症反应的潜在可能性。