1. Academic Validation
  2. Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3

Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3

  • Int J Med Microbiol. 2020 Oct;310(7):151450. doi: 10.1016/j.ijmm.2020.151450.
Chen-Hsun Ho 1 Yu-Chuan Lu 2 Chia-Kwung Fan 3 Hong-Jeng Yu 2 Hsin-Tien Liu 4 Chia-Chang Wu 5 Kuan-Chou Chen 5 Shih-Ping Liu 6 Po-Ching Cheng 7
Affiliations

Affiliations

  • 1 Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
  • 2 Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
  • 3 Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for International Tropical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
  • 6 Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. Electronic address: spliu@ntuh.gov.tw.
  • 7 Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for International Tropical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: bonjovi@tmu.edu.tw.
Abstract

Background: UPEC can internalize clonally in prostate to form biofilm-like intracellular Bacterial communities (IBCs) for recurrent or chronic Infection. We previously indicated that the exposure of prostate cells to testosterone could suppress UPEC invasion and their persistent survival within cells by effectively inhibiting the JAK/STAT1 signaling pathway. However, the regulatory mechanism by which testosterone affects UPEC-induced prostatitis via STAT3, another latent transcription factor signaling pathway is still unclear. The present study aimed to clarify the role of STAT3 in the process of UPEC-induced inflammation and colonization in prostate epithelial cells.

Methods: The effects of testosterone-mediated inhibition were compared between the prostatitis by different UPEC strains (CFT073 and J96) through the specific GFP-UPEC-infected prostate cell model. Fluorescence microscopy was used for UPEC IBCs detection and quantifying, and Flow cytometry, RT-PCR and western blotting were used for analyzing related gene and protein expressions. Pretreatment of JAK and STAT3 inhibitors were also applied to verify the regulation of transduction pathway in testosterone-mediated anti-UPEC Infection.

Results: This study revealed that testosterone effectively suppresses UPEC Infection and IBC formation in prostate cells through the JAK/STAT3 pathway. The results show that CFT073 and J96 UPEC Infection rates and colony numbers were dose-dependently reduced in RWPE-1 cells pretreated with 5 and 20 μg/mL testosterone at 0 and 24 h post-infection. Further, testosterone reduced the amounts of UPEC infecting and surviving within the prostate cells, as well as suppressed the size of IBCs formed. We demonstrated that pretreating testosterone effectively inhibited UPEC Infection along with dose-dependent suppression of STAT3 and the phosphorylated-STAT3 expression in prostate cells, especially in 24 h J96 UPEC infected groups. The STAT Inhibitor, SOCS3 also up-regulated at the same time. In addition, we pretreated the JAK1 or STAT3 Inhibitor with testosterone to block the signaling transduction before CFT073 and J96 UPEC Infection, and found the significant restoring in both the sizes of IBCs and Bacterial numbers in RWPE-1 cells. Therefore, our results suggest that the suppression of STAT3 by testosterone treatment attenuate UPEC growing within IBCs and interfere with their Infection to prostate cells.

Conclusions: Overall, our study demonstrates that testosterone suppresses the initial Infection of prostate epithelial cells by UPEC and reduces the survival of UPEC within IBCs after Infection. These results indicate a critical role for STAT3 in facilitating UPEC Infection and persistence, and its participation in driving testosterone-suppressive responses in prostate epithelial cells. In conclusion, this study suggests that testosterone may be beneficial in treating clinically recurrent UPEC infections and, thus, the persistent recurrence of prostatic inflammation.

Keywords

Intracellular bacterial community; Prostate cell; STAT3; Testosterone; Uropathogenic Escherichia coli.

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