Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: Implications for joint and gut-associated immunopathologies
Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: Implications for joint and gut-associated immunopathologies
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DOI：
10.1016/s1074-7613(00)80038-2
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发表时间：
1999-03-01
期刊：
影响因子：
32.4
通讯作者：
Kollias, G
中科院分区：
文献类型：
--
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
我们解决了从小鼠基因组中删除TNF AU富集元件（ARE）对调节TNF生物合成和宿主生理的影响。ARE的缺乏影响了造血细胞和基质细胞中TNF mRNA不稳定和翻译抑制的机制。在刺激条件下，TNF ARE是缓解和加强信息不稳定和翻译沉默所必需的。此外，突变mRNA不再响应p38和JNK激酶的翻译调节，表明TNF ARE是这些信号的靶点。突变小鼠中两种特定病理的发展，即，慢性炎性关节炎和克罗恩病样炎性肠病，表明ARE功能缺陷可能是类似人类病理发展的病因。
We addressed the impact of deleting TNF AU-rich elements (ARE) from the mouse genome on the regulation of TNF biosynthesis and the physiology of the host. Absence of the ARE affected mechanisms responsible for TNF mRNA destabilization and translational repression in hemopoietic and stromal cells. In stimulated conditions, TNF ARE were required both for the alleviation and reinforcement of message destabilization and translational silencing. Moreover, the mutant mRNA was no longer responsive to translational modulation by the p38 and JNK kinases, demonstrating that TNF ARE are targets for these signals. Development of two specific pathologies in mutant mice, i.e., chronic inflammatory arthritis and Crohn's-like inflammatory bowel disease, suggests that defective function of ARE may be etiopathogenic for the development of analogous human pathologies.