Leukotriene B4-induced changes in vascular permeability are mediated by neutrophil release of heparin-binding protein (HBP/CAP37/azurocidin)

In humans, heparin-binding protein (HBP) and the potent chemotactic lipid leukotriene B-4 (LTB4) are important mediators of innate immune reponses. Here we show that human neutrophils (PMNs) challenged with LTB4 (30 s to 5 min) release HBP as determined by Western blot analysis. This response peaks at 100 nM of agonist and is mediated by the BLT1 receptor. Protein phosphatase-1 (30 mu M) and wortmannin (0.5 mu M) block the LTB4-mediated HBP release from PMNs, which suggests involvement of the 1-phosphatidylinositol 3-kinase intracellular pathway during degranulation. Furthermore, postsecretory supernatants from LTB4-stimulated PMNs induce intracellular calcium mobilization in endothelial cells in vitro and increase in vascular permeability in vivo, as assessed in a mouse model of pleurisy. Selective removal of HBP from the supernatant significantly reduces these activities attributing a key role to HBP in the LTB4-induced change in vascular permeability. This lipid-protein axis could offer novel opportunities for pharmacological intervention in key steps of the vascular response to inflammation.-Di Gennaro, A., Kenne, E., Wan, M., Soehnlein, O., Lindbom, L., Haeggstrom, J. Z. Leukotriene B-4-induced changes in vascular permeability are mediated by neutrophil release of heparin-binding protein (HBP/CAP37/azurocidin). FASEB J. 23, 1750-1757 (2009)