TNF Is Necessary for Castration-Induced Prostate Regression, Whereas TRAIL and FasL Are Dispensable
TNF Is Necessary for Castration-Induced Prostate Regression, Whereas TRAIL and FasL Are Dispensable
复制标题
DOI：
10.1210/me.2010-0312
复制
发表时间：
2011-04-01
影响因子：
--
通讯作者：
Krolewski, John J.
中科院分区：
文献类型：
--
作者：
Davis, Jennifer S.;Nastiuk, Kent L.;Krolewski, John J.
TNF是一种促炎和免疫调节细胞因子，在体外是一种有效的凋亡刺激物。然而，在体内TNF诱导的细胞凋亡的生理作用的例子很少。在这里，我们描述了一个新的作用，TNF在前列腺上皮细胞凋亡后雄激素戒断。采用高分辨率序列磁共振成像来测量小鼠前列腺体积随时间的变化，我们证明去势诱导的前列腺退化的程度显着降低，在小鼠空的TNF或Tnfr 1基因，但不是小鼠缺乏TNF相关的前列腺增生诱导配体或Fas信号。在去势前接受可溶性TNF（sTNF）受体2（以结合TNF并阻断信号传导）的野生型小鼠表现出相同的前列腺消退减少。总之，这些数据表明，在已知的外源性死亡信号中，TNF是去势诱导的前列腺退化所必需的。此外，膜结合的TNF蛋白和基质细胞特异性TNF mRNA水平在去势后大鼠前列腺中增加。这与TNF在前列腺退化中的旁分泌作用一致。当在去势时注射到Tnf（-/-）小鼠的腹膜中时，sTNF恢复前列腺退化的正常水平。然而，在没有去势的情况下接受sTNF的野生型小鼠没有表现出前列腺退化，表明单独的TNF是不够的，而是在额外的去势诱导的信号的背景下起作用。这些发现支持TNF在雄激素戒断后前列腺退化中的生理作用。了解这种作用可能会导致前列腺癌的新疗法。（分子内分泌学25：611-620，2011）
TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal. Employing high-resolution serial magnetic resonance imaging to measure mouse prostate volume changes over time, we demonstrate that the extent of castration-induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes but not mice deficient for TNF-related apoptosis-inducing ligand or Fas signaling. Wild-type mice receiving soluble TNF (sTNF) receptor 2 (to bind TNF and block signaling) before castration exhibit an identical reduction of prostate regression. Together, these data indicate that uniquely among known extrinsic death signals, TNF is required for castration-induced prostate regression. Additionally, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate after castration. This is consistent with a paracrine role for TNF in prostate regression. When injected into the peritoneum of Tnf(-/-) mice at the time of castration, sTNF restores normal levels of prostate regression. However, wild-type mice receiving sTNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient but acts in the context of additional castration-induced signals. These findings support a physiologic role for TNF in prostate regression after androgen withdrawal. Understanding this role may lead to novel therapies for prostate cancer. (Molecular Endocrinology 25: 611-620, 2011)