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) (LTB(4)) are important mediators of innate immune responses. Here we show that human neutrophils (PMNs) challenged with LTB(4) (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 microM) and wortmannin (0.5 microM) block the LTB(4)-mediated HBP release from PMNs, which suggests involvement of the 1-phosphatidylinositol 3-kinase intracellular pathway during degranulation. Furthermore, postsecretory supernatants from LTB(4)-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 LTB(4)-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
Antonio
A
Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Kenne
Ellinor
E
Wan
Min
M
Soehnlein
Oliver
O
Lindbom
Lennart
L
Haeggström
Jesper Z
JZ
D000730:Androstadienes / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000819:agonists; D000077191:Wortmannin
C062991:AZU1 protein, human; D000730:Androstadienes; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C513240:LTB4R protein, human; C485878:LTB4R2 protein, human; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; D000077191:Wortmannin