Pathogenic role of HIF-1 alpha in prostate hyperplasia in the presence of chronic inflammation

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 la (HIP-1 alpha), 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-1 alpha. In the present study, we injected lipopolysaccharide (LPS) into rat prostates to mimic prostatitis and evaluated prostate hyperplasia 14 days later. Epithelial cells of LPS-treated prostates were found to be highly proliferative and HIF-1 alpha 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-1 alpha, and under these conditions IL-1 beta, IL-6, and TNF-alpha cytokines were found to mediate HIF-1 alpha induction. In addition, HIP-la 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-1 alpha 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 HIP-la mediates prostate enlargement under inflammatory conditions, and we suggest that HIF-1 alpha be viewed as a promising target for blocking the transition from prostatitis to BPH. (c) 2012 Elsevier B.V. All rights reserved.