Thromb Haemost 2006; 95(05): 829-835
DOI: 10.1160/TH05-12-0782
Wound Healing and Inflammation/Infection
Schattauer GmbH

Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathway

Sang-Hyun Kwak
1  Divisionof Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
2  Department of Anesthesiology, Chonnam National University Medical School, Gwangju, Korea
,
Xue-Qing Wang
1  Divisionof Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
,
Qianbin He
1  Divisionof Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
,
Wen-Feng Fang
1  Divisionof Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
3  Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
,
Sanchayita Mitra
1  Divisionof Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
,
Khalil Bdeir
4  Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Victoria A. Ploplis
5  W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA; Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas, USA
,
Zhi Xu
5  W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA; Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas, USA
,
Steven Idell
6  Department of Medicine, University of Alabama at Birmingham, Alabama, USA
,
Douglas Cines
4  Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Edward Abraham
6  Department of Medicine, University of Alabama at Birmingham, Alabama, USA
› Author Affiliations
Financial support: This work was supported in part by National Institutes of Health grants HL 76206 and 1 PO1 HL 68743 (to E. Abraham), HL 45018 (to S. Idell), and HL60169, HL66442, and HL67381 (to D. B. Cines).
Further Information

Publication History

Received 02 December 2005

Accepted after resubmission 03 March 2006

Publication Date:
01 December 2017 (online)

Summary

Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen activator (uPA). Although the roles of uPA and PAI-1 in plasmin generation and the degradation of fibrin are well known, recent evidence also suggests that they can participate in acute inflammatory conditions that involve neutrophil activation. In the present experiments, we found that the addition of PAI-1 to LPS-stimulated neutrophils resulted in enhanced nuclear translocation of NF-κB and increased production of the proinflammatory cytokines IL-1β,Tnf-α,and Mip-2.uPA and the kringle domain (KD) of uPA potentiated cytokine expression and NF-κB activation by neutrophils cultured with LPS, and had additive effects when combined with PAI-1. The c-Jun N-terminal kinase (JNK) was activated after exposure of resting neutrophils to PAI-1 or the uPA KD. Enhanced JNK activation, but not that of other kinases induced by LPS, was present in neutrophils cocultured with PAI-1 or uPA KD. Inhibition of JNK activation prevented the potentiation of expression of proinflammatory cytokines induced by PAI-1 or uPA KD in LPS stimulated neutrophils. These results demonstrate that PAI-1 and uPA KD enhance LPSinduced neutrophil responses through their effects on JNK mediated pathways.