Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10

• Published in: PloS one 2010-10, Vol.5 (10), p.e13242
• Main Authors: García-Prieto, Emilio, González-López, Adrián, Cabrera, Sandra, Astudillo, Aurora, Gutiérrez-Fernández, Ana, Fanjul-Fernandez, Miriam, Batalla-Solís, Estefanía, Puente, Xose S, Fueyo, Antonio, López-Otín, Carlos, Albaiceta, Guillermo M
• Format: Article
• Language: English
• Subjects: Animal experimentation; Animals; Bleomycin; Bleomycin - toxicity; Borrelia burgdorferi; Cell Biology/Extra-Cellular Matrix; Chemokines; Collagen; Collagen - metabolism; Collagenase; Cytokines; Cytokines - metabolism; Enzymes; Fibroblasts; Fibrosis; Gelatin - metabolism; Gelatinase B; Genetically modified animals; Genotype & phenotype; Immunology/Immune Response; Inflammation; Interleukin 10; Interleukin-10 - physiology; Interleukins; Lung - drug effects; Lung - pathology; Lung cancer; Lungs; Matrix Metalloproteinase 8 - genetics; Matrix Metalloproteinase 8 - metabolism; Matrix metalloproteinases; Metabolism; Metalloproteinase; Mice; Mice, Knockout; Neutrophil collagenase; Pathogenesis; Pathology; Phosphorylation; Physiological aspects; Pulmonary fibrosis; Respiratory Medicine/Interstitial Lung Diseases; Rodents; Stat3 protein; Synthesis; Trachea; Transforming growth factors; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013242

Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines. To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/-) mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFβ and IL-10 were measured in lung tissue. Mmp8(-/-) mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10) measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures. According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo.