Davis Jennifer S, Nastiuk Kent L, Krolewski John J
Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, California 92697-4800, USA.
Mol Endocrinol. 2011 Apr;25(4):611-20. doi: 10.1210/me.2010-0312. Epub 2011 Feb 3.
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.
肿瘤坏死因子（TNF）是一种促炎和免疫调节细胞因子，在体外是一种强大的凋亡刺激因子。然而，TNF诱导的凋亡在体内的生理作用实例却很少。在此，我们描述了TNF在雄激素撤除后前列腺上皮细胞凋亡中的新作用。利用高分辨率连续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，对于Tnf或Tnfr1基因缺失的小鼠，去势诱导的前列腺萎缩程度显著降低，但对于肿瘤坏死因子相关凋亡诱导配体或Fas信号缺失的小鼠则不然。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程度的前列腺萎缩减少。这些数据共同表明，在已知的外源性死亡信号中，TNF是去势诱导的前列腺萎缩所必需的。此外，去势后大鼠前列腺中膜结合TNF蛋白和基质细胞特异性TNF mRNA水平升高。这与TNF在前列腺萎缩中的旁分泌作用一致。在去势时注射到Tnf(-/-)小鼠腹腔内的sTNF可恢复前列腺萎缩的正常水平。然而，在未去势的情况下接受sTNF的野生型小鼠并未表现出前列腺萎缩，这表明单独的TNF并不足够，而是在其他去势诱导信号的背景下起作用。这些发现支持了TNF在雄激素撤除后前列腺萎缩中的生理作用。了解这一作用可能会带来前列腺癌的新疗法。
