Interleukin-13-dependent expression of matrix metalloproteinase-12 is required for the development of airway eosinophilia in mice.

Abstract

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.