Macrophage Migration Inhibitory Factor Is Induced by Thrombin and Factor Xa in Endothelial Cells

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been shown to play a role in wound-healing processes. In this study, we investigated whether protease-activated receptor (PAR)-1 and PAR-2 mediated MIF expression in human endothelial cells. Thrombin, factor Xa (FXa), and...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-04, Vol.279 (14), p.13729-13737
Main Authors: Shimizu, Tadamichi, Nishihira, Jun, Watanabe, Hirokazu, Abe, Riichiro, Honda, Ayumi, Ishibashi, Teruo, Shimizu, Hiroshi
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - physiology
Factor Xa - pharmacology
Gene Expression - drug effects
Hemostatics - pharmacology
Humans
Macrophage Migration-Inhibitory Factors - genetics
Macrophage Migration-Inhibitory Factors - metabolism
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Peptide Fragments - pharmacology
Receptor, PAR-1 - genetics
Receptor, PAR-1 - metabolism
Receptor, PAR-2 - agonists
Receptor, PAR-2 - genetics
Receptor, PAR-2 - metabolism
RNA, Messenger - analysis
Signal Transduction - drug effects
Signal Transduction - physiology
Thrombin - pharmacology
Umbilical Veins - cytology
Wound Healing - physiology
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Summary:Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been shown to play a role in wound-healing processes. In this study, we investigated whether protease-activated receptor (PAR)-1 and PAR-2 mediated MIF expression in human endothelial cells. Thrombin, factor Xa (FXa), and trypsin induced MIF expression in human dermal microvascular endothelial cells and human umbilical vein endothelial cells, but other proteases, including kallikrein and urokinase, failed to do so. Thrombin-induced MIF mRNA expression was significantly reduced by the thrombin-specific inhibitor hirudin. Thrombin receptor activation peptide-6, a synthetic PAR-1 peptide, induced MIF mRNA expression, suggesting that PAR-1 mediates MIF expression in response to thrombin. The effects of FXa were blocked by antithrombin III, but not by hirudin, indicating that FXa might enhance MIF production directly rather than via thrombin stimulation. The synthetic PAR-2 peptide SLIGRL-NH 2 induced MIF mRNA expression, showing that PAR-2 mediated MIF expression in response to FXa. Concerning the signal transduction, a mitogen-activated protein kinase kinase inhibitor (PD98089) and a nuclear factor (NF)-κB inhibitor (SN50) suppressed the up-regulation of MIF mRNA in response to thrombin, FXa, and PAR-2 agonist stimulation, whereas a p38 inhibitor (SB203580) had little effect. These facts indicate that up-regulation of MIF by thrombin or FXa is regulated by p44/p42 mitogen-activated protein kinase-dependent pathways and NF-κB-dependent pathways. Moreover, we found that PAR-1 and PAR-2 mRNA expression in endothelial cells was enhanced by MIF. Furthermore, we examined the inflammatory response induced by PAR-1 and PAR-2 agonists injected into the mouse footpad. As shown by footpad thickness, an indicator of inflammation, MIF-deficient mice (C57BL/6) were much less sensitive to either PAR-1 or PAR-2 agonists than wild-type mice. Taken together, these results suggest that MIF contributes to the inflammatory phase of the wound healing process in concert with thrombin and FXa via PAR-1 and PAR-2.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M400150200