Combined treatment with dihydrotestosterone and lipopolysaccharide modulates prostate homeostasis by upregulating TNF-alpha from M1 macrophages and promotes proliferation of prostate stromal cells

Androgens and chronic inflammation, which play essential roles in the development of benign prostatic hyperplasia (BPH), are considered to be important factors in disorders of prostate homeostasis. These two factors may lead to pathological hyperplasia in the prostate transition zone of patients with BPH. However, few studies have examined the mechanism of how dihydrotestosterone (DHT) affects chronic inflammation in prostate tissue during the progression of BPH. This study examined the performance of DHT in lipopolysaccharide-treated M1 macrophages and the subsequent effects on the proliferation of prostate stromal and epithelial cells. We found that DHT increased secretion of the pro-inflammatory factor tumor necrosis factor (TNF)-alpha from M1 macrophages differentiated from THP-1 cells. The supernatant of M1 macrophages promoted the proliferation of WPMY-1 prostate stromal cells by upregulating B-cell lymphoma-extra large (Bcl-xL) and cellular Myc (c-Myc) levels by activating TNF-alpha-mediated nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) pathways. Moreover, this supernatant increased the expression of androgen receptor in WPMY-1 cells, which was TNF-alpha-independent. Additionally, TNF-alpha protein expression was significantly higher in patients with BPH and a large prostate volume than that in those with a small prostate volume. Further analysis showed that higher serum testosterone combined with prostate-specific androgen concentrations was related to TNF-alpha expression. This study suggests that DHT modulates the inflammatory environment of BPH by increasing TNF-alpha expression from lipopolysaccharide-treated M1 macrophages and promotes the proliferation of prostate stromal cells. Targeting TNF-alpha, but not DHT, may be a promising strategy for patients with BPH.

Automated summary

The study demonstrates that DHT increases TNF-α expression from lipopolysaccharide-treated M1 macrophages, promoting proliferation of prostate stromal cells. TNF-α mediates the activation of NF-kappa B and MAPK pathways, affecting the differentiation and proliferation of prostate cells.