Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway
Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway
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DOI：
10.1073/pnas.1511380113
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发表时间：
2016-02-16
影响因子：
11.1
通讯作者：
Sweetser, David A.
中科院分区：
文献类型：
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作者：
Ramasamy, Selvi;Saez, Borja;Sweetser, David A.
Tle1（split 1 的转导蛋白样增强子）是一种辅阻遏物，可与多种 DNA 结合转录因子相互作用，并与许多细胞功能有关；然而，生理学研究是有限的。 Tle1缺陷（Tle1（Delta/Delta））小鼠虽然出生时基本正常，但表现出皮肤缺陷、肺发育不全、严重奔跑、身体状况不佳和早期死亡。 Tle1(Delta/Delta) 小鼠表现出慢性炎症表型，皮肤、肺和肠中炎症细胞因子和趋化因子表达增加，循环 IL-6 和 G-CSF 增加，同时造血向粒细胞、巨噬细胞祖细胞和骨髓细胞转变。 Tle1(Delta/Delta) 巨噬细胞响应 Toll 样受体 (TLR) 激动剂和脂多糖 (LPS) 产生增加的炎症细胞因子，并且 Tle1(Delta/Delta) 小鼠对耳部皮肤 12-O-tetradecanoylphorbol-13-acetate 治疗表现出增强的炎症反应。 Tle1 的缺失不仅会导致促炎性 NF-kappa B 的磷酸化和激活增加，还会导致 Hes1（多毛的和 split-1 的增强子）减少，Hes1 是巨噬细胞炎症的负调节因子。此外，Tle1(Delta/Delta) 小鼠表现出 B6-F10 黑色素瘤异种移植物的加速生长。据我们所知，我们的工作提供了第一个体内证据，证明 TLE1 是炎症的主要反调节因子，在多种炎症性疾病和癌症进展中具有潜在作用。
Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1(Delta/Delta)) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1(Delta/Delta) mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1(Delta/Delta) macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1(Delta/Delta) mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-kappa B but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1(Delta/Delta) mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.