期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 28, 页码 20745-20757出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.410720
关键词
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资金
- National Institutes of Health [2R01ES015981-06, R01ES014871]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Grant [1BX001135-01]
Macrophages not only initiate and accentuate inflammation after tissue injury, but they are also involved in resolution and repair. This difference in macrophage activity is the result of a differentiation process to either M1 or M2 phenotypes. M1 macrophages are pro-inflammatory and have microbicidal and tumoricidal activity, whereas the M2 macrophages are involved in tumor progression and tissue remodeling and can be profibrotic in certain conditions. Because mitochondrial Cu, Zn-superoxide dismutase (Cu, Zn-SOD)-mediated H2O2 is crucial for development of pulmonary fibrosis, we hypothesized that Cu, Zn-SOD modulated the macrophage phenotype. In this study, we demonstrate that Cu, Zn-SOD polarized macrophages to an M2 phenotype, and Cu, Zn-SOD-mediated H2O2 levels modulated M2 gene expression at the transcriptional level by redox regulation of a critical cysteine in STAT6. Furthermore, overexpression of Cu, Zn-SOD in mice resulted in a profibrotic environment and accelerated the development of pulmonary fibrosis, whereas polarization of macrophages to the M1 phenotype attenuated pulmonary fibrosis. Taken together, these observations provide a novel mechanism of Cu, Zn-SOD-mediated and Th2-independent M2 polarization and provide a potential therapeutic target for attenuating the accelerated development of pulmonary fibrosis.
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