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Published online before print July 20, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0305158

Received for publication March 18, 2005.
Revised May 26, 2005.
Accepted for publication June 11, 2005.

Article

The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with _V3 integrins

Sang-Hyun Kwak ^*, Sanchayita Mitra ^*, Khalil Bdeir , Derek Strassheim ^*, Jong Sung Park ^*, Jael Yeol Kim ^*, Steven Idell ^¶, Douglas Cines , and Edward Abraham ^*@

*Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver; Department of Anesthesiology, Chonnam National University Medical School, Gwangju, Korea; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; Department of Internal Medicine, Chung Ang University College of Medicine, Seoul, Korea; and ^¶Department of Specialty Care Services, The University of Texas Health Center at Tyler

^@ To whom correspondence should be addressed. E-mail: edward.abraham{at}uchsc.edu.

	Abstract

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-1, macrophage-inflammatory protein-2, and tumor necrosis factor , 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 _V or ₃ integrins or to the combination of _V3 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 _V3 integrins, potentiates neutrophil activation.

Key Words: uPA • IL-1 • MIP-2 • TNF- • growth factor domain

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