Increased cyclooxygenase activity impairs apoptosis of inflammatory neutrophils in mice lacking gelatinase B/matrix metalloproteinase-9.
Matrix metalloproteinase-9 (MMP-9)/gelatinase B plays an important role in neutrophil infiltration during inflammation and cyclooxygenases (COX-1 and COX-2) and their products are important regulators of inflammation. Recently, we reported that a genetic lack of MMP-9 impairs neutrophil infiltration during early zymosan-induced peritonitis but at later stages (> 24 hr) neutrophils persist in the peritoneal cavity. Here we show that this is the result of impaired apoptosis of MMP-9(-/-)-derived leucocytes. As enhanced COX-1 expression was reported in MMP-9(-/-) mice, we evaluated the hypothesis that altered COX expression induced the above phenomenon as COX-dependent prostaglandins can act either anti-apoptotically (PGE(2)) or pro-apoptotically (PGD(2)). The current data demonstrate that messenger RNA and protein expression of both COX isoforms and their activities are increased in MMP-9(-/-) mice during late peritonitis. Application of selective COX inhibitors revealed enhanced COX-1-dependent PGE(2) production and impaired COX-2-dependent PGD(2) synthesis in MMP-9(-/-) mice. Most importantly, inhibition of COX-1 abolished prolonged neutrophil accumulation in the peritoneal cavity of MMP-9(-/-) mice and increased apoptosis of inflammatory leucocytes. Similarly, weaker apoptosis of MMP-9(-/-) bone marrow neutrophils treated in vitro with zymosan was reversed by COX-1 inhibition. In conclusion, enhanced COX-1 expression is responsible for persistent neutrophil presence in the peritoneum of MMP-9(-/-) mice because of increased synthesis of anti-apoptotic PGE(2). In non-transgenic mice, however, inflammatory leucocytes die apoptotically in the late stages of peritonitis as a result of COX-2-dependent PGD(2) activity. Overall, we show a dependence of COX expression on the presence of MMP-9.
Kolaczkowska
Elzbieta
E
Department of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, Krakow, Poland. ela.kolaczkowska@uj.edu.pl
Plytycz
Barbara
B
Arnold
Bernd
B
Piccard
Helene
H
Opdenakker
Ghislain
G
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051545:Cyclooxygenase 1 / Q000096:biosynthesis* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology*; D015230:Prostaglandin D2 / Q000032:analysis; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; C115461:SC 560; D013876:Thiophenes; C064874:DuP 697; D015054:Zymosan; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone; D015230:Prostaglandin D2