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

Abstract

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.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…In line with those findings, the neutrophil secretagog activity of LTB 4 has consistently been observed at higher LTB 4 concentrations compared with those needed to induce chemotaxis (Serhan et al, 1982). For example, maximal release of ␣-defensins from neutrophils was observed at 100 nM LTB 4 , and the release of azurocidin was gradually increased at LTB 4 concentrations ranging from 10 nM to 1 M (Di Gennaro et al, 2009). The latter apparent low-affinity response, however, was inhibited by the selective BLT 1 R antagonist CP-105,696, but not by the selective BLT 2 R antagonist LY255238.…”

“…In addition to chemotaxis, LTB 4 stimulates neutrophil release of lysozyme (Hafstrom et al, 1981), matrix metalloproteinases (MMP) (Kjeldsen et al, 1992), myeloperoxidase , elastase, ␣-defensins , and azurocidin (Di Gennaro et al, 2009). Initial characterization of the binding of [ 3 H]LTB 4 in relation to the functional effects of LTB 4 on human neutrophils suggested that whereas high-affinity binding sites mediated chemotaxis, this lysosomal degranulation occurred by LTB 4 binding to low-affinity sites (Goldman and Goetzl, 1984).…”

Differential Effects of Arachidonic and Eicosapentaenoic Acid-Derived Eicosanoids on Polymorphonuclear Transmigration Across Endothelial Cell Cultures

“…Findings that suggest that LTB 4 -induced increase in endothelial permeability is related to PMN adhesion, PMN activation, and probably mediator release by PMN, but not by LTB 4 , have a direct effect, in agreement with Di Gennaro et al (2009), who reported an indirect activity of LTB 4 , on vessel wall barrier function, with heparin-binding protein playing the role of effector molecule. In this way, the effects of a COX inhibitor and EP 1 and EP 2 antagonists suggest the participation of PGE 2 through EP 1 /EP 2 interaction in these events, and consequently the interplay of PGE 2 /PGE 3 in the effects of LTB 4 /LTB 5 on endothelial permeability in a coculture model of endothelial and PMN cells.…”

Ccl2 and Ccl3 Mediate Neutrophil Recruitment via Induction of Protein Synthesis and Generation of Lipid Mediators

“…12 Our in vivo data clearly demonstrate that the Ccl2/JE/ MCP-1-and Ccl3/MIP-1␣-induced microvascular leakage strictly requires protein synthesis, endogenous generation of leukotrienes as well as PAF, and, above all, the presence of neutrophils. Moreover, microvascular leakage elicited by PAF and LTB 4 themselves has also been found to be neutrophil-dependent 25,26 indicating that in Ccl2/JE/MCP-1-and Ccl3/MIP-1␣-elicited inflammation secondarily generated lipid mediators induce extravasation of neutrophils which, in turn, promote the microvascular leakage. Thereby, transmigrating neutrophils are suggested to disrupt endothelial junctions as well as to degrade the perivascular basement membrane as it has been supposed for different inflammatory reactions.…”