Abstract
Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate-specific markers and proteins including cytoskeleton (α-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN-γ+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll-like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-γ+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future.
Highlights
Benign prostatic hyperplasia (BPH) represents the most common urologic disease among elderly men, in which the incidence is over 70% at age 60 years and over 90% at age 70 years [1, 2]
Primary prostate stromal cells rapidly lose its phenotypes during passages, especially the decreased expression of androgen receptors (AR), which exert an essential role in inducing the inflammatory responses [21, 22]
Successful immortalization was confirmed by stable expression of HPV-16 E6/ E7 mRNA in immortalized hPSC (ihPSC) cells by Reverse transcriptase polymerase chain reaction (RT-PCR) (Fig 1B)
Summary
Benign prostatic hyperplasia (BPH) represents the most common urologic disease among elderly men, in which the incidence is over 70% at age 60 years and over 90% at age 70 years [1, 2]. There is increasing evidence for the association of chronic prostate inflammation with BPH [3,4,5]. Inflammation in BPH tissue includes the up-regulation of pro-inflammatory cytokines such as IL-17 in infiltrating T cells [6], interferon-γ in basal and stromal cells [7], and IL8 in epithelial cells [8]. A variety of growth factors and cytokines have been implicated in BPH inflammation, such as IL-1, IL-6, IL-8, and IL-17 as well as TNF-α and TGF-β [9]. Preventing or reducing prostate inflammation might be one strategy for reducing the risk of prostate cancer (PC) and targeting inflammation sources is considered as an attractive option. Therapeutic strategy of targeting the prostate stoma, especially the prostate stromal cells, has become emerged
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