Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC226
HIF-1α mediates prostate hyperplasia under chronic inflammation
H. Kim1, J. Park1,3, Y. Chun1,2
1. Department of Biomedical Sciences, Seoul National University, Seoul, Korea, Republic of. 2. Physiology, Seoul National University, Seoul, Korea, Republic of. 3. Ischemic/Hypoxic Disease Institute, Seoul National University, Seoul, Korea, Republic of.
Benign prostatic hyperplasia (BPH) commonly occurs in aged men, and concurrently with chronic prostatitis. Although inflammatory signs are frequently found in BPH specimens, it is unclear if inflammation initiates or aggravates BPH. Recently, we reported that HIF-1α is involved in testosterone-induced prostate hyperplasia and that the HIF-1α inhibition blocks the disease progress. Given that the HIF-1α synthesis is facilitated by proinflammatory cytokines, we here tested the possibility that the cytokines are secreted from immune cells infiltrating into the prostate and enlarges the prostate by upregulating HIF-1α. All animal procedures were performed in accord with the Seoul National University Laboratory Animal Maintenance Manual. To examine whether the prostate becomes hyperplastic under inflammatory conditions, we treated rat prostates with LPS in vivo. We injected 150 μl of LPS (0.1 μg/g body weight) or vehicle (DMSO) into the prostates of rats which had been anesthetized by isoflurane (2% for 10 min). The same procedure was done again 7 days later. On the seventh day after the second injection, each rat was killed by CO2 asphyxiation, and then the prostate was excised. We found that HIF-1α was upregulated in the epithelial cells of LPS-treated prostates. Moreover, cell proliferation was promoted, and cell death was demoted in the prostates. To understand the mechanism underlying the LPS-induced induction of HIF-1α, we directly treated PNT2 (human BPH cell line) or LNCaP (prostate cancer cell line) cells with LPS (5 μg/ml), but HIF-1α was not significantly induced. Interestingly, HIF-1α and VEGF expressions were highly induced in prostate cells which had been cultured in the conditioned media obtained from LPS (0.1 μg/ml)-activated THP-1 macrophages. We further studied to identify the cytokines responsible for HIF-1α induction, and also to clarify the mechanism by which HIF-1α induces prostate overgrowth under inflammatory circumstances.
Where applicable, experiments conform with Society ethical requirements