Interleukin-13-dependent expression of matrix metalloproteinase-12 is required for the development of airway eosinophilia in mice.
We investigated the expression and function of matrix metalloproteinase-12 (MMP-12) in a model of allergic airway inflammation. Mice were sensitized mucosally by exposure to aerosolized ovalbumin (OVA) daily over a period of 10 d in the context of adenovirus-mediated granulocyte macrophage colony-stimulating factor (GM-CSF) expression. The ensuing inflammatory response is characterized by a Th2 cytokine profile, OVA-specific IgE, and airway eosinophilia. Using real-time, quantitative reverse transcriptase-polymerase chain reaction we assessed MMP-12 mRNA expression in whole lung tissue. We observed a 12- and 70-fold increase in expression at Days 7 and 11, respectively, in OVA-exposed mice when compared with naive controls. Immunoblot analysis revealed an increase in MMP-12 protein in the bronchoalveolar lavage fluid of mice exposed to OVA in the context of GM-CSF. No such elevation was observed in mice exposed to saline only in the context of GM-CSF. To assess functional role of MMP-12, MMP-12 knockout (KO) mice were subjected to the aforementioned protocol. We observed an 80% reduction in eosinophils in the bronchoalveolar lavage fluid of KO mice compared with their wild-type littermates. Using interleukin-13 KO mice, we demonstrated that expression of MMP-12 is interleukin-13-dependent. Collectively, our data indicate a novel function for MMP-12 in the process of airway eosinophil accumulation.
Pouladi
Mahmoud A
MA
McMaster University, Department of Pathology and Molecular Medicine, Health Sciences Centre, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. stampfli@mcmaster.ca
Robbins
Clinton S
CS
Swirski
Filip K
FK
Cundall
Meghan
M
McKenzie
Andrew N J
AN
Jordana
Manel
M
Shapiro
Steven D
SD
Stämpfli
Martin R
MR
D000818:Animals; D001483:Base Sequence; D001980:Bronchi / Q000201:enzymology* / Q000473:pathology; D017931:DNA Primers; D004802:Eosinophilia / Q000201:enzymology* / Q000473:pathology; D005260:Female; D018793:Interleukin-13 / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout
D017931:DNA Primers; D018793:Interleukin-13; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12