Kinin B1 receptor activation turns on exocytosis of matrix metalloprotease-9 and myeloperoxidase in human neutrophils: involvement of mitogen-activated protein kinase family.
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.
Ehrenfeld
Pamela
P
Laboratorio de Patologia Celular, Instituto de Anatomía, Histología and Patología, Universidad Austral de Chile, Valdivia, Chile.
Matus
Carola E
CE
Pavicic
Francisca
F
Toledo
Cesar
C
Nualart
Francisco
F
Gonzalez
Carlos B
CB
Burgos
Rafael A
RA
Bhoola
Kanti D
KD
Figueroa
Carlos D
CD
D003572:Cytochalasins / Q000494:pharmacology; D005089:Exocytosis; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D019950:Mitogen-Activated Protein Kinase 1 / Q000097:blood; D048052:Mitogen-Activated Protein Kinase 3 / Q000097:blood; D020928:Mitogen-Activated Protein Kinases / Q000097:blood*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D009195:Peroxidase / Q000097:blood*; D010766:Phosphorylation; D043783:Receptor, Bradykinin B1 / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000097:blood* / Q000502:physiology; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D003572:Cytochalasins; D043783:Receptor, Bradykinin B1; D043562:Receptors, G-Protein-Coupled; D009195:Peroxidase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9