Published online before print December 16, 2008
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*Department of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University Krakow, Poland; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands; Laboratory for Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; and Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Belgium
@ To whom correspondence should be addressed. E-mail: ela.kolaczkowska{at}uj.edu.pl.
Extracellular proteolysis of basement membranes and matrix is required for leukocyte diapedesis and migration to the inflammatory focus. Neutrophil elastase (NE) and matrix metalloproteinases (MMPs) are among the enzymes involved in these processes, as shown in mice genetically deprived of such enzymes. However, studies with MMP-9-/- mice revealed that albeit neutrophil influx is impaired initially in these animals versus controls, neutrophilia is subsequently augmented during later stages of zymosan peritonitis. MMP-9 as a MMP and NE as a serine protease belong to different enzyme classes. As MMP-9 and NE are produced by neutrophils and have similar biological effects on matrix remodeling, it was evaluated whether enhanced NE activity might compensate for the lack of MMP-9. In genetically uncompromised mice, two waves of NE expression and activity during zymosan peritonitis were observed in inflammatory neutrophils and macrophages at the time of influx of the respective cell populations into the peritoneum. Additionally, NE expression was associated with the activity of resident peritoneal mast cells and macrophages, as their depletion reduced NE activity. Most importantly, the NE mRNA and protein expression and activity were enhanced significantly in MMP-9-/- mice during late stages of zymosan peritonitis. In addition, the application of a selective NE inhibitor restrained enhanced neutrophil accumulation significantly. In conclusion, during acute peritoneal inflammation, NE expression and activity increase gradually, facilitating leukocyte influx. Moreover, increased NE activity might compensate for a genetic lack of MMP-9 (as detected in MMP-9-/- mice), resulting in delayed accumulation of neutrophils during late zymosan peritonitis.
Key Words: gelatinase B • peritoneal inflammation • macrophages • mast cells
