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Increased matrix metalloproteinase-9 concentration and activity after stimulation with interleukin-17 in mouse
O Prause1, S Bozinovski, G P Anderson
1Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Institute of Internal Medicine, Göteborg University, Gothenburg, Sweden. olof.prause@lungall.gu.se
Background:
The proteolytic enzyme matrix metalloproteinase (MMP)-9 can degrade structural compounds such as the extracellular matrix and the basement membrane in the airways and lungs. MMP-9 has therefore been implicated in remodelling of the airways and lungs during severe asthma and chronic obstructive pulmonary disease (COPD).
Methods:
The effect of the T lymphocyte derived proinflammatory cytokine interleukin (IL)-17 on MMP-9 protein release and activity in the airways was studied in vivo and in vitro.
Results:
In vivo, intranasal stimulation of mice with IL-17 induced the release of the precursor molecule proMMP-9 in bronchoalveolar lavage (BAL) fluid, associated with a pronounced local accumulation of neutrophils that stained positive for MMP-9. Stimulation with IL-17 also increased the concentration of free soluble MMP-9 that was proteolytically active as determined by a gelatinase substrate assay. The concentration of MMP-9 in BAL fluid had a strong positive correlation with the number of neutrophils; the amount of MMP-9 per neutrophil was not increased by IL-17 stimulation. In vitro, stimulation of mouse neutrophils with IL-17 did not increase the concentration of proMMP-9 in the conditioned medium.
Conclusion:
Local stimulation with IL-17 increases the concentration of biologically active MMP-9 as well as its precursor molecule in mouse airways in vivo. This increase in proteolytic load is probably mainly due to an increased number of neutrophils and not to an increase in the release of MMP-9 from each neutrophil. These findings indicate a link between the T lymphocyte cytokine IL-17 and increased proteolytic load in the airways which may be relevant for chronic inflammatory airway diseases such as severe asthma and COPD.
Insights
Interleukin-17 (IL-17) increases active matrix metalloproteinase-9 (MMP-9) in mouse airways, primarily by recruiting more neutrophils. This suggests a link between IL-17 and airway remodeling in severe asthma and COPD.
Area of Science:
- Pulmonary immunology
- Protease biology
Background:
- Matrix metalloproteinase (MMP)-9 degrades airway extracellular matrix.
- MMP-9 is implicated in airway remodeling in severe asthma and COPD.
Purpose of the Study:
- To investigate the effect of interleukin (IL)-17 on MMP-9 release and activity in airways.
Main Methods:
- In vivo intranasal stimulation of mice with IL-17.
- In vitro stimulation of mouse neutrophils with IL-17.
- Analysis of MMP-9 precursor (proMMP-9) and active MMP-9 in bronchoalveolar lavage (BAL) fluid.
- Neutrophil quantification and MMP-9 staining.
Main Results:
- IL-17 induced proMMP-9 release and active MMP-9 in mouse BAL fluid.
- IL-17 increased neutrophil accumulation, correlating with MMP-9 levels.
- MMP-9 levels per neutrophil did not increase; in vitro neutrophil stimulation with IL-17 did not enhance proMMP-9 release.
Conclusions:
- Local IL-17 stimulation increases active MMP-9 and its precursor in mouse airways.
- Increased MMP-9 is mainly due to neutrophil recruitment, not enhanced release per neutrophil.
- IL-17 links to increased airway proteolytic load, relevant to severe asthma and COPD.
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