Kinin B1 receptor activation turns on exocytosis of matrix metalloprotease-9 and myeloperoxidase in human neutrophils: involvement of mitogen-activated protein kinase family

Abstract

During neutrophil activation and degranulation, MMP-9 and MPO are released into the extracellular space to propagate inflammatory disorders. As kinin peptides are major participants in acute inflammatory responses, and the G-protein-coupled B(1)R mediates the chemotaxis of human neutrophils, we examined the release of the neutrophil enzymes MMP-9 and MPO by the B(1)R agonist LDBK and determined the signaling pathways that may regulate this cellular effect. Cytochalasin-treated and -untreated neutrophils were suspended in HBSS and stimulated with a range concentration of LDBK for 5 min. Zymography and Western blotting revealed that LDBK induced the release of MMP-9 and MPO. The use of specific signaling transduction inhibitors showed that release of MMP-9 depended on ERK1/2 and p38 MAPKs, whereas release of MPO involved only the p38 cascade. Inhibition of the key steps in these pathways showed that the release of both enzymes depended on PKC and PI3K. Stimulation of neutrophils with LDBK produced phosphorylation of ERK1/2 and p38 MAPK, which was inhibited by B(1)R antagonists. The phosphorylated ERK1/2 MAPK translocated to the neutrophil nucleus, suggesting that transcription of new genes may follow activation of B(1)R. Our results demonstrate that in human neutrophils, activation of kinin B(1)R by LDBK initiates separate signaling cascades that trigger the release of MMP-9 and MPO from tertiary and primary granules, respectively, suggesting that the B(1)R plays a pivotal role in inflammatory disorders.

Phosphatase Wip1 Negatively Regulates Neutrophil Migration and Inflammation

“…It is reported that the activated NF-kB by TNF-a could directly interact with the promoter region of the human MMP-9 gene (44). p38 MAPK is closely involved in the expression of MMP-9, MPO, superoxide, and elastase in neutrophils or B-CLL cells (45)(46)(47)(48). Thus, we conclude that the enhanced function of Wip1-deficient neutrophils may be mainly mediated by the increased p38 MAPK-STAT1 and NF-kB pathways.…”

10 Kallikrein-Kinin Cascade: Bioregulation by Human Tissue Kallikrein 1 (hK1, KLK1)

“…Previous studies have shown that thrombin causes the release of various enzymes from human neutrophils, including elastase, at the moment at which they attach to the endothelium (Toothill et al, 1990). Recently, we have shown that stimulation of human neutrophils with the natural B 1 R ligand results in the release of matrix metalloproteinase-9 (MMP-9) by a mechanism that depends on the phosphorylation of ERK1/2 and p38 MAPK in a cascade that involves protein kinase C and phosphoinositide-3 kinase (Ehrenfeld et al, 2009). MMP-9 is an extensively glycosylated enzyme, abundantly expressed in tertiary granules of human neutrophils, and is considered a key enzyme that degrades type-IV collagen, the major protein component of basement membranes that provide the molecular network support for endothelial cells.…”

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

“…MPO may contribute to plaque destabilization through the activation of MMPs and inactivation of their inhibitors, resulting in degradation of the fibrous cap matrix. Activation of human neutrophils can result in the simultaneous release of MPO and active MMP-9 [86], suggesting that MPO may activate MMPs upon degranulation. Indeed, low concentrations of HOCl have been reported to directly activate MMP-7 in vitro by oxidation of the thiol moiety of the MMP cysteine switch domain [57].…”