Interleukin-8 Induced Biology in Benign Prostatic Hyperplasia

点击翻译按钮获取中文摘要

Benign prostatic hyperplasia (BPH) is a common age-associated disorder 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 of tenascin. IL-8 is a potent chemokine that induces chemotaxis of many cell types stimulates reactive stroma / wound repair mechanisms. We have generated a transgenic mouse expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and stromal phenotype with elevated tenascin-C and pro-collagen I expression. Our preliminary data suggests that reactive stroma is recruited from both local tissue-fixed and circulating marrow-derived CD34+ progenitor fibrocyte 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. Together, these studies will pinpoint the role of IL-8 in recruiting reactive stroma and inducing the hyerplastic phenotype. The purpose of this project is to provide proof of concept and key data, from which to build a strategic approach to support clinical trials. The long-range goal of this work is to develop a novel therapeutic strategy that targets components of the IL-8 / CXCR2 regulatory pathway for the treatment of BPH.