细胞凋亡
细胞生物学
运输机
化学
生物物理学
生物
生物化学
基因
作者
Lang Chen,Lang Chen,Hongwei Yi,Hongwei Yi,Qingtian Li,Qingtian Li,Tianhao Duan,Tianhao Duan,Xin Liu,Xin Liu,Linfeng Li,Lin-Feng Li,Helen Y. Wang,Helen Y. Wang,Changsheng Xing,Changsheng Xing,Rong Fu Wang,Rong Fu Wang,Rong Fu Wang,Rong Fu Wang
标识
DOI:10.1002/advs.202401654
摘要
Abstract T‐bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T‐bet in non‐immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet‐O‐T‐bet transgenic mouse strain is generated for doxycycline‐inducible T‐bet expression in adult animals. Unexpectedly, ubiquitous T‐bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell‐type‐specific analyses reveal that T‐bet‐driven pathology is not attributable to its overexpression in CD4 + T cells or myeloid lineages. Instead, inducible T‐bet overexpression in the intestinal epithelial cells is the critical determinant of the observed lethal phenotype. Mechanistically, T‐bet overexpression modulates ion channel and transporter profiles in gut epithelial cells, triggering profound fluid secretion and subsequent lethal dehydration. Furthermore, ectopic T‐bet expression enhances gut epithelial cell apoptosis and markedly suppresses colon cancer development in xenograft models. Collectively, the findings unveil a previously unrecognized role of T‐bet in intestinal epithelial cells for inducing apoptosis, diarrhea, and local inflammation, thus implicating its potential as a therapeutic target for the treatment of cancer and inflammatory diseases.
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