McIlwain David W, Zoetemelk Marloes, Myers Jason D, Edwards Marshé T, Snider Brandy M, Jerde Travis J
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
Inholland University, Hoofddorp, Netherlands.
Prostate. 2016 Jun;76(8):722-34. doi: 10.1002/pros.23161. Epub 2016 Feb 24.
Both prostate cancer and benign prostatic hyperplasia are associated with inflammatory microenvironments. Inflammation is damaging to tissues, but it is unclear how the inflammatory microenvironment protects specialized epithelial cells that function to proliferate and repair the tissue. The objective of this study is to characterize the cell death and cell survival response of the prostatic epithelium in response to inflammation.
We assessed induction of cell death (TNF, TRAIL, TWEAK, FasL) and cell survival factors (IGFs, hedgehogs, IL-6, FGFs, and TGFs) in inflamed and control mouse prostates by ELISA. Cell death mechanisms were determined by immunoblotting and immunofluorescence for cleavage of caspases and TUNEL. Survival pathway activation was assessed by immunoblotting and immunofluorescence for Mcl-1, Bcl-2, Bcl-XL, and survivin. Autophagy was determined by immunoblotting and immunofluorescence for free and membrane associated light chain 3 (LC-3).
Cleavage of all four caspases was significantly increased during the first 2 days of inflammation, and survival protein expression was substantially increased subsequently, maximizing at 3 days. By 5 days of inflammation, 50% of prostatic epithelial cells expressed survivin. Autophagy was also evident during the recovery phase (3 days). Finally, immunofluorescent staining of human specimens indicates strong activation of survival proteins juxtaposed to inflammation in inflamed prostate specimens.
The prostate responds to deleterious inflammation with induction of cell survival mechanisms, most notably survivin and autophagy, demonstrating a coordinated induction of survival factors that protects and expands a specialized set of prostatic epithelial cells as part of the repair and recovery process during inflammation.
前列腺癌和良性前列腺增生均与炎症微环境相关。炎症对组织具有损害作用，但尚不清楚炎症微环境如何保护具有增殖和修复组织功能的特殊上皮细胞。本研究的目的是描述前列腺上皮细胞在炎症反应中的细胞死亡和细胞存活反应。
我们通过酶联免疫吸附测定法评估了炎症小鼠前列腺和对照小鼠前列腺中细胞死亡诱导因子（肿瘤坏死因子、肿瘤坏死因子相关凋亡诱导配体、肿瘤坏死因子样弱凋亡诱导因子、Fas配体）和细胞存活因子（胰岛素样生长因子、刺猬因子、白细胞介素-6、成纤维细胞生长因子和转化生长因子）。通过免疫印迹和免疫荧光检测半胱天冬酶的切割情况及TUNEL法来确定细胞死亡机制。通过免疫印迹和免疫荧光检测髓细胞白血病-1、B细胞淋巴瘤-2、B细胞淋巴瘤-extra-large和生存素，评估存活信号通路的激活情况。通过免疫印迹和免疫荧光检测游离及与膜相关的轻链3（LC-3）来确定自噬情况。
在炎症的前两天，所有四种半胱天冬酶的切割均显著增加，随后存活蛋白表达大幅增加，在第3天达到最大值。到炎症第5天时，50%的前列腺上皮细胞表达生存素。自噬在恢复阶段（第3天）也很明显。最后，人类标本的免疫荧光染色表明，在炎症前列腺标本中，存活蛋白的强烈激活与炎症并存。
前列腺通过诱导细胞存活机制，尤其是生存素和自噬，对有害炎症做出反应，这表明在炎症期间的修复和恢复过程中，存活因子的协同诱导可保护并扩增一组特殊的前列腺上皮细胞。
