Regulation of leukocyte recruitment by polypeptides derived from high molecular weight kininogen

被引:55
作者
Chavakis, T
Kanse, SM
Pixley, RA
May, AE
Isordia-Salas, I
Colman, RW
Preissner, KT
机构
[1] Univ Giessen, Fachbereich Humanmed, Inst Biochem, D-35392 Giessen, Germany
[2] Univ Giessen, Dept Internal Med 3, D-35392 Giessen, Germany
[3] Temple Univ, Sch Med, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19122 USA
[4] Tech Univ Munich, Deutsch Herzzentrum, D-8000 Munich, Germany
关键词
HK; monoclonal antibody; leukocyte; Mac-1;
D O I
10.1096/fj.01-0201com
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Proteolytic cleavage of single-chain, high molecular weight kininogen (HK) by kallikrein releases the short-lived vasodilator bradykinin and leaves behind a two-chain, high molecular weight kininogen (HKa) reported to bind to the beta2-integrin Mac-1 (CR3, CD11b/CD18, alphaM beta2) on neutrophils and exert antiadhesive properties by binding to the urokinase receptor (uPAR) and vitronectin. We define the molecular mechanisms for the antiadhesive effects of HK related to disruption of beta2-integrin-mediated cellular interactions in vitro and in vivo. In a purified system, HK and HKa inhibited the binding of soluble fibrinogen and ICAM-1 to immobilized Mac-1, but not the binding of ICAM-1 to immobilized LFA-1 (CD11a/CD18, alphaL beta2). This inhibitory effect could be attributed to HK domain 5 and to a lesser degree to HK domain 3, consistent with the requirement of both domains for binding to Mac-1. Accordingly, HK, HKa, and domain 5 inhibited the adhesion of Mac-1 but not LFA-1-transfected K562 human erythroleukemic cells to ICAM-1. Moreover, adhesion of human monocytic cells to fibrinogen and to human endothelial cells was blocked by HK, HKa, and domain 5. By using peptides derived from HK domain 5, the sequences including amino acids H475-G497 (and to a lesser extent, G440-H455) were identified as responsible for the antiadhesive effect, which was independent of uPAR. Finally, administration of domain 5 into mice, followed by induction of thioglycollate-provoked peritonitis, decreased the recruitment of neutrophils by A similar to 70% in this model of acute inflammation. Taken together, HKa (and particularly domain 5) specifically interacts with Mac-1 but not with LFA-1, thereby blocking Mac-1-dependent leukocyte adhesion to fibrinogen and endothelial cells in vitro and in vivo and serving as a novel endogenous regulator of leukocyte recruitment into the inflamed tissue.
引用
收藏
页码:2365 / 2376
页数:12
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