Pathogenic role of HIF-1α in prostate hyperplasia in the presence of chronic inflammation
Pathogenic role of HIF-1α in prostate hyperplasia in the presence of chronic inflammation
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DOI：
10.1016/j.bbadis.2012.09.002
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发表时间：
2013-01-01
影响因子：
6.2
通讯作者：
Chun, Yang-Sook
中科院分区：
文献类型：
--
作者：
Kim, Hye-Jin;Park, Jong-Wan;Chun, Yang-Sook
良性前列腺增生（BPH）通常发生在老年男性慢性前列腺炎。虽然BPH经常伴有炎症，但尚不清楚炎症是否是前列腺肥大的基础。最近，我们报道了缺氧诱导因子Ia（HIP-1 α），这是已知的促炎细胞因子诱导，参与睾酮诱导的前列腺增生。因此，我们假设炎症条件下浸润的巨噬细胞分泌的细胞因子通过上调HIF-1 α刺激前列腺肥大。在本研究中，我们将脂多糖（LPS）注射到大鼠前列腺中以模拟前列腺炎，并在14天后评估前列腺增生。发现LPS处理的前列腺的上皮细胞高度增殖，并且前列腺组织中的HIF-1 α水平升高。当前列腺上皮细胞在LPS活化的巨噬细胞的条件培养基中孵育时，它们强烈表达HIF-1 α，并且在这些条件下，发现IL-1 β、IL-6和TNF-α细胞因子介导HIF-1 α诱导。此外，发现HIP-la增强Twist的表达，Twist启动上皮-间充质转化（EMT）。此外，在LPS处理的大鼠前列腺中观察到深刻的EMT特征，并且发现天然HIF-1 α抑制剂抗坏血酸盐和姜黄素在体内和体外都能减弱EMT和前列腺增生。基于这些结果，我们提出HIP-la在炎症条件下介导前列腺增大，并且我们建议HIF-1 α被视为阻断前列腺炎向BPH转变的有希望的靶点。(c)2012爱思唯尔有限公司版权所有。
Benign prostatic hyperplasia (BPH) commonly occurs in older men with chronic prostatitis. Although BPH is frequently accompanied by inflammation, it is unclear whether inflammation underlies prostate enlargement. Recently, we reported that hypoxia-inducible factor la (HIP-1 alpha), which is known to be induced by proinflammatory cytokines, is involved in testosterone-induced prostate hyperplasia. Therefore, we hypothesized that cytokines secreted from infiltrated macrophages under inflammatory conditions stimulate prostate enlargement by up-regulating HIF-1 alpha. In the present study, we injected lipopolysaccharide (LPS) into rat prostates to mimic prostatitis and evaluated prostate hyperplasia 14 days later. Epithelial cells of LPS-treated prostates were found to be highly proliferative and HIF-1 alpha levels in prostate tissues to be elevated. When prostate epithelial cells were incubated in conditioned medium from macrophages activated with LPS, they robustly expressed HIF-1 alpha, and under these conditions IL-1 beta, IL-6, and TNF-alpha cytokines were found to mediate HIF-1 alpha induction. In addition, HIP-la was found to enhance the expression of Twist, which initiates epithelial-mesenchymal transition (EMT). Furthermore, profound EMT features were observed in LPS-treated rat prostates, and the natural HIF-1 alpha inhibitors ascorbate and curcumin were found to attenuate EMT and prostate hyperplasia both in vivo and in vitro. Based on these results, we propose that HIP-la mediates prostate enlargement under inflammatory conditions, and we suggest that HIF-1 alpha be viewed as a promising target for blocking the transition from prostatitis to BPH. (c) 2012 Elsevier B.V. All rights reserved.