期刊
ONCOTARGET
卷 6, 期 32, 页码 32980-33005出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5431
关键词
Barrett's esophagus; myeloid-derived suppressor cells (MDSC); IL-17; S100A9; IL-1 beta
资金
- NCI BETRNet program [CA163004]
- NIH K26 career development award [OD 012097]
- NCI Program Project [PO1 CA098101]
- Molecular Biology and Imaging, Cell Culture, Molecular Biology and Transgenic and Chimeric Mouse Core Facilities of the Center for Molecular Studies in Digestive and Liver Disease at the University of Pennsylvania [PO1 CA098101, P30-DK050306]
Cdx2, an intestine specific transcription factor, is expressed in Barrett's esophagus (BE). We sought to determine if esophageal Cdx2 expression would accelerate the onset of metaplasia in the L2-IL-1 beta transgenic mouse model for Barrett's-like metaplasia. The K14-Cdx2::L2-IL-1 beta double transgenic mice had half as many metaplastic nodules as control L2-IL-1 beta mice. This effect was not due to a reduction in esophageal IL-1 beta mRNA levels nor diminished systemic inflammation. The diminished metaplasia was due to an increase in apoptosis in the K14-Cdx2:: L2-IL-1 beta mice. Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+cells that are significantly reduced in K14-Cdx2:: L2-IL-1 beta mice. These cells have features of immature granulocytes and have immune-suppressing capacity. We demonstrate that the apoptosis in K14-Cdx2:: L2-IL-1 beta mice is CD8+T cell dependent, which CD11b+Gr-1+cells are known to inhibit. Lastly, we show that key regulators of CD11b+Gr-1+cell development, IL-17 and S100A9, are significantly diminished in the esophagus of K14-Cdx2:: L2-IL-1 beta double transgenic mice. We conclude that metaplasia development in this mouse model for Barrett's-like metaplasia requires suppression of CD8+cell dependent apoptosis, likely mediated by immune-suppressing CD11b+Gr-1+immature myeloid cells.
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