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Development of Neutrophile Regulatory Peptides with Receptor Association Structures

具有受体缔合结构的中性粒细胞调节肽的开发

基本信息

批准号：
18550154
负责人：
KODAMA Hiroaki
金额：
$ 2.64万
依托单位：
Saga University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Neutrophil functions including chemotaxis, degranulation, and generation of superoxide anion are modulated by diverse extracellular agonists such as N-formyl-methionyl-leucyl-phenylalanine (fMLP). Formyl peptide receptor (FPR) and formyl peptide receptor-like 1 (FPRL1), a superfamily of seven transmembrane (TM) proteins, are expressed on human neutrophils as the fMLP binding receptors. We found that human neutrophils pretreated with human formyl peptide receptor transmembrane (hFPRTM) peptides were enhanced superoxide anion production when stimulated with fMLP. However, a membrane protein interacting with hFPRTM peptides is not identified. To explore the sequence dependences of the TM peptides for neutrophil proming activities, peptides possess the TM sequences of formyl peptide receptor (FPR), FPR like 1 receptor (FPRL1), and GABA receptor were synthesized by solid-phase method with Fmoc chemistry. Homogeneities and structures of synthetic peptides were confirmed by HPLC and MALDI-TOF MS. The biological activities of synthetic peptides were carried out as superoxide production for human neutrophils. Neutrophils treated with TM peptides from FPR and FPRL1 produced 2-3 folds of superoxide anion by the treatment of fMLP, neutrophil agonist. TM peptide from GABA receptor exhibited no significant priming activity. These results suggested the priming effect of TM peptide for neutrophil was sequence dependence and it required the FPR related sequences.

中性粒细胞功能包括趋化性、脱粒和超氧阴离子的产生由多种细胞外激动剂如N-甲酰基-甲硫氨酰基-亮氨酰基-苯丙氨酸（fMLP）调节。甲酰基肽受体（FPR）和甲酰基肽受体样1（FPRL 1）是7种跨膜（TM）蛋白的超家族，作为fMLP结合受体在人嗜中性粒细胞上表达。我们发现，人中性粒细胞预处理与人甲酰肽受体跨膜（hFPRTM）肽增强超氧阴离子的产生时，刺激fMLP。然而，与hFPR ™肽相互作用的膜蛋白未被鉴定。为了探索TM肽对中性粒细胞促敏活性的序列依赖性，采用Fmoc化学固相法合成了具有甲酰肽受体（FPR）、FPR样1受体（FPRL 1）和GABA受体TM序列的肽。通过HPLC和MALDI-TOF MS证实了合成肽的均一性和结构。用来自FPR和FPRL 1的TM肽处理的中性粒细胞产生的超氧阴离子是中性粒细胞激动剂fMLP处理的2-3倍。来自GABA受体的TM肽没有表现出明显的启动活性。这些结果提示TM肽对中性粒细胞的启动作用是序列依赖性的，它需要FPR相关序列。