title: Pathogenic role of HIF-1α in prostate hyperplasia in the presence of chronic inflammation.
abstract: 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 1α (HIF-1α), 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-1α. In the present study, we injected lipopolysaccharide (LPS) into rat prostates to mimic prostatitis and evaluated prostate hyperplasia 14days later. Epithelial cells of LPS-treated prostates were found to be highly proliferative and HIF-1α 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-1α, and under these conditions IL-1β, IL-6, and TNF-α cytokines were found to mediate HIF-1α induction. In addition, HIF-1α 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-1α 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 HIF-1α mediates prostate enlargement under inflammatory conditions, and we suggest that HIF-1α be viewed as a promising target for blocking the transition from prostatitis to BPH.
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Cho
authors.forename: Chung-Hyun
authors.initials: CH
authors.lastname: Cho
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Kim
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Shin
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
authors.forename: Sang Jeong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha