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

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.

Keywords

PAI-1 - Tnf-alpha - JNK kinase - neutrophil

• References

• 1 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383: 441-3.
• 2 Nassar T, Haj-Yehia A, Akkawi A. et al. Binding of urokinase to low density lipoprotein-related receptor (LRP) regulates vascular smooth muscle cell contraction. J Biol Chem 2002; 277: 40499-504.
• 3 Zhang J-C, Sakthivel R, Kniss D. et al. The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells. J Biol Chem 1998; 273: 32273-80.
• 4 Pralong GT, Calandra MP, Glauser J. et al. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-62.
• 5 Rubenfeld GD, Caldwell E, Peabody E. et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353: 1685-93.
• 6 Idell S. Extravascular coagulation and fibrin deposition in acute lung injury. New Horiz 1994; 02: 566-74.
• 7 Idell S. Endothelium and disordered fibrin turnover in the injured lung: newly recognized pathways. Crit Care Med 2002; 30: S274-280.
• 8 Philippe JF, Offner PJ, Declerck G. et al. Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemost 1991; 65: 291-5.
• 9 Idell S, Peterson BT, Gonzalez KK. et al. Local abnormalities of coagulation and fibrinolysis and alveolar fibrin deposition in sheep with oleic acid-induced lung injury. Am Rev Respir Dis 1988; 138: 1282-94.
• 10 Quax PH, van den Hoogen CM, Verheijen J. et al. Endotoxin induction of plasminogen activator and plasminogen activator inhibitor type 1 mRNA in rat tissues in vivo. J Biol Chem 1990; 265: 15560-3.
• 11 Salat CP, Boekstegers E, Holler K. et al. Hemostatic parameters in sepsis patients treated with anti-TNF alpha-monoclonal antibodies. Shock 1996; 06: 233-7.
• 12 Shetty S, Bdeir K, Cines DB. et al. Induction of plasminogen activator inhibitor-1 by urokinase in lung epithelial cells. J Biol Chem 2003; 278: 18124-31.
• 13 Hermans PW, Hibberd ML, Booy R. et al. 4G/5G promoter polymorphism in the plasminogen-activatorinhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 1999; 354: 556-60.
• 14 Menges TP, Hermans W, Little SG. et al. Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 2001; 357: 1096-7.
• 15 Rijneveld AW, Levi M, Florquin S. et al. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J Immunol 2002; 168: 3507-11.
• 16 May AE, Kanse SM, Lund LR. et al. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo. J Exp Med 1998; 188: 1029-37.
• 17 Hansen AP, Petros AM, Meadows RP. et al. Solution structure of the amino-terminal fragment of urokinase-type plasminogen activator. Biochemistry 1994; 33: 4847-64.
• 18 Gudewicz PW, Gilboa N. Human urokinase-type plasminogen activator stimulates chemotaxis of human neutrophils. Biochem Biophys Res Commun 1987; 147: 1176-81.
• 19 Odekon LE, Gilboa N, Del Vecchio P. et al. Urokinase in conditioned medium from phorbol ester-pretreated endothelial cells promotes polymorphonuclear leukocyte migration. Circ Shock 1992; 37: 169-75.
• 20 Abraham E, Gyetko MR, Kuhn K. et al. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. J Immunol 2003; 170: 5644-51.
• 21 Kwak SH, Mitra S, Bdeir K. et al. The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with αVβ3 integrins. J Leukoc Biol 2005; 78: 937-45.
• 22 Blasi F. uPA, uPAR, PAI-1: key intersection of proteolytic, adhesive and chemotactic highways?. Immunol Today 1997; 18: 415-7.
• 23 Gyetko MR, Sitrin RG, Fuller JA. et al. Function of the urokinase receptor (CD87) in neutrophil chemotaxis. J Leukoc Biol 1995; 58: 533-8.
• 24 Cao D, Mizukami IF, Garni-Wagner BA. et al. Human urokinase-type plasminogen activator primes neutrophils for superoxide anion release. Possible roles of complement receptor type 3 and calcium. J Immunol 1995; 154: 1817-29.
• 25 Gyetko MR, Sud S, Kendall T. et al. Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection. J Immunol 2000; 165: 1513-9.