Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8⁺ T cells in benign prostatic hyperplasia

Abstract

Background Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men, but the underlying pathophysiological mechanisms are complex and not fully understood. Phosphodiesterase type 5 inhibitors (PDE5‐Is) used to treat BPH could upregulate the cyclic guanosine monophosphate (cGMP)‐dependent protein kinase G (PKG) signaling, which was shown to blunt inflammation in the prostate. Our previous findings indicate that CD8+ T cells promote the proliferation of BPH epithelial cells (BECs) in low androgen conditions through secretion of CCL5; however, the role of the cGMP/PKG pathway in the process is unclear. Methods Paraffin‐embedded tissues were used for expression quantity of CD8+ T cells, CCL5, cyclin D1, and PDE5 protein by immunohistology in prostate specimens which were/were not treated with finasteride 5 mg daily for at least 6 months before surgery. BPH‐1 cells were cocultured with or without CD8 + T cells or PDE5‐Is in low androgen conditions for 4 days. The conditioned media, BPH‐1 cells, and CD8 + T cells were harvested for the subsequent experiments. The quantitative polymerase chain reaction was used for assaying the level of messenger RNA expression of CCL5. CCL5 in the conditioned media was detected by the enzyme‐linked immunosorbent assay. The effect of PDE5‐Is on cocultured BPH‐1/CD8 + T‐cell proliferation was detected by the cell counting kit‐8. A high‐fat diet (HFD)‐induced prostatic hyperplasia rat model was used to investigate the effect of cGMP/PKG activation in CD8 + T cells in vivo. Results CD8+ T‐cell infiltration into human BPH tissues was positively correlated with the expression of CCL5, cyclin D1, and PDE5, whereas in an HFD‐induced prostatic hyperplasia rat model, the activation of the cGMP/PKG signaling by a PDE5‐I could suppress the CD8 + T‐cell infiltration and the CCL5 and cyclin D1 expression. Furthermore, the activation of the cGMP/PKG pathway inhibited CCL5 secretion by CD8 + T cells by downregulating nuclear factor‐κB p65 phosphorylation, which reduced the growth of BPH‐1 through CCL5/STAT5/CCND1 signaling. Conclusions Our results indicate that the upregulation of the cGMP/PKG/p65 signaling reduces CCL5 secretion in CD8 + T cells, which in turn decreases the proliferation of BECs in low androgen conditions, suggesting that the combination of 5α reductase inhibitors lowering androgen levels and PDE5‐Is may be a novel, more effective treatment for BPH patients.

RETRACTED: Attenuation of Benign Prostatic Hyperplasia by Optimized Tadalafil Loaded Pumpkin Seed Oil-Based Self Nanoemulsion: In Vitro and In Vivo Evaluation

“…A significant decrease in prostate weight and index by 35.51% and 36.71%, respectively, was noted in the co-treatment groups using doses of optimized TDL-loaded PSO SNEDDS when compared to the testosterone-only group. PDE5 inhibitors, as TDL, have been reported to decrease the proliferation of prostate cells, while also decreasing the number of smooth muscle cells (SMCs) in the prostate, bladder, neck, and supporting vasculature [5,9,10]. In addition, a previous study has revealed improvement in symptoms of BPH for patients receiving PSO and/or saw palmetto oil [20,21,24].…”

“…Pharmacokinetic data revealed a 2.3-fold increase of TDL concentration, from optimized TDL-PSO SNEDDS, in the prostate compared with the raw TDL group. This study indicated that the combination of TDL and PSO in an optimized TDL PSO SNEDDS formula improved the efficacy of TDL in the management of BPH.Pharmaceutics 2019, 11, 640 2 of 13 PDE5 also elevates the amount of blood reaching the lower urinary tract, while influencing the afferent nerve activity of the bladder [5,9,10]. Moreover, bladder performance can be impacted by functional and structural variations in the prostate, bladder, and the vasculature supporting such structures [11].…”

“…These changes include overactivity of the autonomic nervous system, pelvic ischemia, a decrease in pelvic nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling, atherosclerosis, and elevated Rho-kinase activity (which results in control of myosin phosphatase activity and, therefore, facilitates smooth prostatic muscle contractions) [3]. Several research studies suggest an elevated expression of phosphodiesterase type 5 (PDE5) to be present in the lower part of the urinary tract and the supporting vasculature [4][5][6][7][8]. Furthermore, inhibition of PDE5 has been observed to decrease the proliferation of prostate cells, while also decreasing the number of smooth muscle cells (SMCs) in the prostate, bladder, neck, and supporting vasculature.…”

“…Pharmaceutics 2019, 11, 640 2 of 13 PDE5 also elevates the amount of blood reaching the lower urinary tract, while influencing the afferent nerve activity of the bladder [5,9,10]. Moreover, bladder performance can be impacted by functional and structural variations in the prostate, bladder, and the vasculature supporting such structures [11].…”

Inflammation is a target of medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia

“…Moreover, in human BPH stromal cell lines, tadalafil blunted IL-8 secretion induced by metabolic stimuli or TNF-α [ 5 , 40 , 43 ]. In tissue of men with LUTS/BPH under low androgen conditions (i.e., treated with finasteride), tadalafil was able to reduce T-cell infiltration and related CCL5 secretion resulting in decreased proliferation of BPH epithelial cells [ 44 ].…”