Increased Infiltrated Macrophages in Benign Prostatic Hyperplasia (BPH)
Increased Infiltrated Macrophages in Benign Prostatic Hyperplasia (BPH)
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DOI：
10.1074/jbc.m112.355164
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发表时间：
2012-04
期刊：
影响因子：
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通讯作者：
Xiaohai Wang;Wen-Jye Lin;K. Izumi;Qi Jiang;K. Lai;Defeng Xu;Lei-Ya Fang;T. Lu;Lei Li;Shujie Xia;Chawnshang Chang
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文献类型：
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作者：
Xiaohai Wang;Wen-Jye Lin;K. Izumi;Qi Jiang;K. Lai;Defeng Xu;Lei-Ya Fang;T. Lu;Lei Li;Shujie Xia;Chawnshang Chang
背景：巨噬细胞是良性前列腺增生症(BPH)发病机制中的关键细胞。但是，巨噬细胞促进前列腺细胞增殖的分子机制尚不清楚。结果：巨噬细胞可通过雄激素受体(AR)-CCL3依赖的途径促进前列腺基质细胞的生长。结论：CCL3是巨噬细胞促进前列腺基质细胞生长的AR下游调节因子。意义：AR和CCL3可能成为治疗BPH的新的治疗方法的机会靶点。浸润性巨噬细胞可能在良性前列腺增生症(BPH)的发生和发展中起重要作用，但其潜在的机制仍不清楚。我们发现巨噬细胞在人和小鼠BPH组织中的浸润增加。通过建立共培养的Transwell系统，我们发现在共培养过程中巨噬细胞的迁移和前列腺基质细胞的增殖增加。重要的是，间质雄激素受体(AR)可以促进巨噬细胞的迁移和巨噬细胞介导的间质细胞增殖。我们确定CCL3是AR下游的参与者，并发现CCL3在人和小鼠BPH前列腺中的水平显著增加。在小鼠BPH模型中，切除前列腺间质AR显著降低了前列腺中CCL3的表达水平。一直以来，通过AR降解增强剂ASC-J9§靶向AR，或用抗体中和CCL3，都能抑制巨噬细胞迁移和前列腺基质细胞生长。我们的研究提供了巨噬细胞通过间质AR/CCL3信号通路调节前列腺间质细胞的机械性见解，这可能有助于开发治疗方法来对抗持续炎症的BPH。
Background: Macrophages are key players in the pathogenesis of benign prostatic hyperplasia (BPH). But, molecular mechanisms by which macrophages promote prostate cell proliferation remain unclear. Results: Macrophages can enhance the growth of prostate stromal cells via an androgen receptor (AR)-CCL3-dependent pathway. Conclusion: CCL3 is an AR downstream regulator of macrophages in promoting prostate stromal cell growth. Significance: AR and CCL3 could be targets of opportunity for new therapeutic approaches for the treatment of BPH. Infiltrated macrophages may play important roles in the development and progression of benign prostatic hyperplasia (BPH), but the underlying mechanisms remain largely unknown. We found increased macrophages infiltration in human and mouse BPH tissues. By establishing a co-culture transwell system, we found increased migration of macrophages and proliferation of prostate stromal cells during co-culture. Importantly, stromal androgen receptor (AR) could enhance the migration of macrophages and macrophage-mediated stromal cell proliferation. We identified CCL3 as an AR downstream player, and found CCL3 levels were notably increased in human and mouse BPH prostates. Ablation of prostate stromal AR in a mouse BPH model significantly reduced CCL3 expression levels in prostates. Consistently, targeting AR via an AR degradation enhancer, ASC-J9§, or neutralization of CCL3 with an antibody, resulted in suppression of macrophage migration and prostate stromal cell growth. Our study provides mechanistic insights on the regulation of prostate stromal cells by macrophages via stromal AR/CCL3 signaling pathways, which could potentially allow the development of therapeutic approaches for battling BPH with persistent inflammation.