Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells
Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells
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DOI：
10.1530/joe-12-0142
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发表时间：
2012-07-01
影响因子：
4
通讯作者：
Maggi, Mario
中科院分区：
文献类型：
--
作者：
Vignozzi, Linda;Cellai, Ilaria;Maggi, Mario
良性前列腺增生（BPH）的进展涉及慢性炎症和免疫失调。临床前研究表明，前列腺炎症和组织重塑会因性腺功能减退而加剧，并可通过补充睾酮来预防。我们现在调查，在人类中，性腺功能减退症是否与更严重的BPH炎症和选择性雄激素受体激动剂双氢睾酮（DHT）对来自BPH患者（hBPH）的基质细胞培养物的体外作用。对前列腺增生患者前列腺切除术标本中的炎性浸润进行组织学分析，并与血清睾酮水平进行相关性分析。即使在调整混杂因素后，性腺功能减退症与前列腺内炎症风险增加5倍相关，这也比在性腺正常的BPH患者中观察到的更严重。通过炎症刺激物（肿瘤坏死因子α、脂多糖或CD 4（+）T细胞）触发hBPH细胞诱导炎症/生长因子（白细胞介素6（IL 6）、IL 8和碱性成纤维细胞生长因子（bFGF））的大量分泌。CD 4（+）T细胞与hBPH细胞的共培养诱导Th 1诱导物（IL 12）、Th 1募集趋化因子（干扰素γ诱导蛋白10，IP 10）以及Th 2（IL 9）和Th 17（IL 17）特异性细胞因子的分泌。用DHT预处理抑制NF-κ B活化并抑制几种炎症/生长因子的分泌，其中对IL 8、IL 6和bFGF的作用最显著。减少睾酮细胞产生的炎性细胞因子，IL 10的增加，和睾酮细胞增殖的显着减少表明，DHT对睾酮细胞产生广泛的抑制作用。总之，我们的数据表明，DHT对人前列腺基质细胞发挥免疫调节作用，抑制其积极诱导和/或维持自身免疫和炎症反应的潜力。内分泌学杂志（2012）214，31-43
Progression of benign prostatic hyperplasia (BPH) involves chronic inflammation and immune dysregulation. Preclinical studies have demonstrated that prostate inflammation and tissue remodeling are exacerbated by hypogonadism and prevented by testosterone supplementation. We now investigated whether, in humans, hypogonadism was associated with more severe BPH inflammation and the in vitro effect of the selective androgen receptor agonist dihydrotestosterone (DHT) on cultures of stromal cells derived from BPH patients (hBPH). Histological analysis of inflammatory infiltrates in prostatectomy specimens from a cohort of BPH patients and correlation with serum testosterone level was performed. Even after adjusting for confounding factors, hypogonadism was associated with a fivefold increased risk of intraprostatic inflammation, which was also more severe than that observed in eugonadal BPH patients. Triggering hBPH cells by inflammatory stimuli (tumor necrosis factor alpha, lipopolysaccharide, or CD4(+)T cells) induced abundant secretion of inflammatory/growth factors (interleukin 6 (IL6), IL8, and basic fibroblast growth factor (bFGF)). Co-culture of CD4(+)T cells with hBPH cells induced secretion of Th1 inducer (IL12), Th1-recruiting chemokine (interferon gamma inducible protein 10, IP10), and Th2 (IL9)- and Th17 (IL17)-specific cytokines. Pretreatment with DHT inhibited NF-kappa B activation and suppressed secretion of several inflammatory/growth factors, with the most pronounced effects on IL8, IL6, and bFGF. Reduced inflammatory cytokine production by testosterone cells, an increase in IL10, and a significant reduction of testosterone cells proliferation suggested that DHT exerted a broad antiinflammatory effect on testosterone cells. In conclusion, our data demonstrate that DHT exerts an immune regulatory role on human prostatic stromal cells, inhibiting their potential to actively induce and/or sustain autoimmune and inflammatory responses. Journal of Endocrinology (2012) 214, 31-43