Dataset Information

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-?B 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 5? reductase inhibitors lowering androgen levels and PDE5-Is may be a novel, more effective treatment for BPH patients.

SUBMITTER: Jin S

PROVIDER: S-EPMC6593656 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Activation of cGMP/PKG/p65 signaling associated with PDE5-Is downregulates CCL5 secretion by CD8 <sup>+</sup> T cells in benign prostatic hyperplasia.

Jin Song S Xiang Peng P Liu Jie J Yang Yang Y Hu Shuai S Sheng Jindong J He Qun Q Yu Wei W Han Wenke W Jin Jie J Peng Jing J

The Prostate 20190408 8

<h4>Background</h4>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<sup>+</sup> T cells promote the proliferati ...[more]

PMID: 30958912

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Project description:BackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

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Project description:BackgroundThe volume and thickness of intravesical prostatic protrusion and other characteristics of benign prostatic hyperplasia have not been investigated. We determine the effects of age and prostate volume on anatomical features of benign prostatic hyperplasia using three-dimensional measurement in this study.MethodsThis retrospective study included a total of 98 patients with benign prostatic hyperplasia. Three-dimensional models of prostate, central gland, peripheral zone, intravesical prostatic protrusion, prostatic urethra and bladder were reconstructed according to pelvic T2-weighted magnetic resonance imaging of these patients. The models were used to measure the intravesical prostatic protrusion volume, intravesical prostatic protrusion thickness, intravesical prostatic protrusion index, intravesical prostatic protrusion, prostate volume, peripheral zone volume, peripheral zone thickness, peripheral zone index, prostatic urethra thickness, the angle and distance of distal prostatic urethra with regard to coronal plane and sagittal plane and so on.ResultsIntravesical prostatic protrusion volume, intravesical prostatic protrusion thickness and peripheral zone volume of prostate volume >80 mL group were significantly higher than these in prostate volume <80 mL group (P<0.001, 0.01, 0.01, respectively). These parameters significantly increased with age (P<0.001, 0.01, 0.05, respectively). Peripheral zone index was significantly lower of prostate volume >80 mL group than these in prostate volume <80 mL group (P<0.05). Peripheral zone index significantly decreased with age (P<0.01). Intravesical prostatic protrusion index had no significant difference in all age groups. Peripheral zone thickness and prostatic urethra thickness had no significant difference in all groups. The distance and angle of distal prostatic urethra prostatic urethra with regard to coronal plane were significantly higher than these with regard to sagittal plane (both P<0.001).ConclusionsThe rearward slope of the prostatic urethra is greater than the left or right offset during the process of benign prostatic hyperplasia. Three-dimensional measurement provides good supports for further clinical and scientific research.

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

Activation of cGMP/PKG/p65 signaling associated with PDE5-Is downregulates CCL5 secretion by CD8 <sup>+</sup> T cells in benign prostatic hyperplasia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

Activation of cGMP/PKG/p65 signaling associated with PDE5-Is downregulates CCL5 secretion by CD8 <sup>+</sup> T cells in benign prostatic hyperplasia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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