Interleukin-8 Induced Biology in Benign Prostatic Hyperplasia

描述（由申请人提供）：良性前列腺增生（BPH）的典型特征是上皮和间质增生以及前列腺的进行性增大。前列腺增生与慢性炎症有关，但具体机制尚不清楚。我们已经报道了增生性BPH上皮过度表达白细胞介素-8 (IL-8)，这与肌成纤维细胞反应性基质表型显著相关，并改变了腱素的表达模式。IL-8是一种有效的趋化因子，可诱导骨髓源性细胞趋化并刺激反应性基质/伤口修复机制。我们建立了一个过表达IL-8的人类异种移植物模型和表达KC （IL-8的小鼠同源物）的转基因小鼠系，并观察到IL-8（KC）诱导的增生上皮和反应性基质表型，tenascin-C和前胶原i升高。我们的初步数据表明，反应性基质可能来自循环骨髓衍生祖纤维细胞（CD14+）细胞。我们的假设是，升高的IL-8可以激活和/或募集腺性BPH病灶处的反应性基质祖细胞，而这种增生的反应性基质进一步推动了BPH的腺性和间质增生。为了解决这一假设，提出了三个具体目标：1。表征IL-8(KC) / CXCR2信号和tenascin-C作为下游效应物在前列腺增生诱导中的作用。2. 目的探讨IL-8 / CXCR2受体信号在反应性基质祖细胞募集中的作用。3. 利用药物诱导基因表达靶向反应性基质细胞中的IL-8(KC) / CXCR2信号通路，解除信号通路耦联，从而减弱BPH中反应性基质和上皮增生的发生。该项目的目的是确定IL-8在募集反应性基质中的作用的基本机制，并建立概念证明，反应性基质祖细胞和随后的反应性基质可以靶向解耦关键通路，以减轻增生性表型。

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) is typified by epithelial and stromal hyperplasia and progressive enlargement of the prostate gland. BPH is associated with chronic inflammation, however specific mechanisms are unknown. We have reported that hyperplastic BPH epithelium overexpresses interleukin-8 (IL-8) and that this correlated significantly with a myofibroblast reactive stroma phenotype with altered expression patterns of tenascin. IL-8 is a potent chemokine that induces chemotaxis of marrow-derived cells and stimulates reactive stroma / wound repair mechanisms. We have generated a human xenograft model that overexpresses IL-8 and transgenic mouse lines expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and reactive stroma phenotype induced by IL-8(KC) with elevated tenascin-C and pro- collagen I. Our preliminary data suggests that reactive stroma may be recruited from circulating marrow- derived progenitor fibrocyte (CD14+) cells. It is our hypothesis that elevated IL-8 functions to activate and/or recruit reactive stroma progenitor cells at foci of glandular BPH and that this hyperplastic reactive stroma further drives BPH glandular and stromal hyperplasia. To address this hypothesis three Specific Aims are proposed: 1. To characterize the role of IL-8(KC) / CXCR2 signaling and tenascin-C, as a downstream effector, in the induction of prostate hyperplasia. 2. To determine the role of IL-8 / CXCR2 receptor signaling in the recruitment of reactive stroma progenitor cells. 3. To target IL-8(KC) / CXCR2 signaling in reactive stroma cells using drug-inducible gene expression to uncouple signaling and therefore attenuate the genesis of reactive stroma and epithelial hyperplasia in BPH. The purpose of this project is to determine basic mechanisms of IL-8 action in recruiting reactive stroma and establish proof-of-concept that reactive stroma progenitor cells and subsequent reactive stroma can be targeted to uncouple key pathways in order to attenuate the hyperplastic phenotype. PUBLIC HEALTH RELEVANCE: This objective of this study is to determine how interleukin-8 (IL-8) regulates the biology of benign prostatic hyperplasia. This project will provide data on key mechanisms and pathways using several model systems. These mechanisms and pathways may evolve as therapeutic targets.