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The kringle domain of urokinase‐type plasminogen activator potentiates LPS‐induced neutrophil activation through interaction with α V β 3 integrins
Author(s) -
Kwak SangHyun,
Mitra Sanchayita,
Bdeir Khalil,
Strassheim Derek,
Park Jong Sung,
Kim Jael Yeol,
Idell Steven,
Cines Douglas,
Abraham Edward
Publication year - 2005
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0305158
Subject(s) - kringle domain , proinflammatory cytokine , plasminogen activator , plasmin , biology , integrin , serine protease , urokinase , cytokine , lipopolysaccharide , tumor necrosis factor alpha , chemokine , microbiology and biotechnology , chemistry , immunology , inflammation , biochemistry , receptor , protease , endocrinology , enzyme , genetics
Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. In addition, uPA has been shown to have proinflammatory properties, particularly in potentiating lipopolysaccharide (LPS)‐induced neutrophil responses. To explore the mechanisms by which uPA exerts these effects, we examined the ability of specific uPA domains to increase cytokine expression in murine and human neutrophils stimulated with LPS. Whereas the addition of intact uPA to neutrophils cultured with LPS increased mRNA and protein levels of interleukin‐1β, macrophage‐inflammatory protein‐2, and tumor necrosis factor α, deletion of the kringle domain (KD) from uPA resulted in loss of these potentiating effects. Addition of purified uPA KD to LPS‐stimulated neutrophils increased cytokine expression to a degree comparable with that produced by single‐chain uPA. Inclusion of the arginine‐glycine‐aspartic but not the arginine‐glycine‐glutamic peptide to neutrophil cultures blocked uPA kringle‐induced potentiation of proinflammatory responses, demonstrating that interactions between the KD and integrins were involved. Antibodies to α V or β 3 integrins or to the combination of α V β 3 prevented uPA kringle‐induced enhancement of expression of proinflammatory cytokines and also of adhesion of neutrophils to the uPA KD. These results demonstrate that the KD of uPA, through interaction with α V β 3 integrins, potentiates neutrophil activation.