Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathwayFinancial 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).
02 December 2005
Accepted after resubmission 03 March 2006
01 December 2017 (online)
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.
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