Research Article: Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway

Date Published: June 30, 2017

Publisher: Public Library of Science

Author(s): Chen-Hsun Ho, Chia-Kwung Fan, Hong-Jeng Yu, Chia-Chang Wu, Kuan-Chou Chen, Shih-Ping Liu, Po-Ching Cheng, Praveen Thumbikat.


Prostatitis is a common condition in adult men of all ages. Uropathogenic Escherichia coli (UPEC) are most frequent pathogen involved in bacterial prostatitis by refluxing the infected urine into prostatic ducts and resulting in an ascending urethral infection. However, the study about the mechanisms of UPEC to invade, replicate and persist in normal prostate epithelial cell is only few. Given the fact that UPEC is pathogen most frequently involved in prostatitis and that testosterone has been demonstrated to attenuate prostate inflammation caused by other etiologies. In this study we investigated whether the testosterone reduces the prostatitis and related mechanism by regulating IFN-γ/STAT1 signaling pathway. In the current study aimed to clarify whether testosterone influences the process of UPEC-induced prostate inflammation and invasion into the prostate epithelial cells. In addition, we set up a normal prostate cell model for UPEC infection to evaluate the ability to invade the urothelial cells as well as the colonization of intercellular bacterial communities in vitro. By using the model, we examine the effects of testosterone to suppress effectively the invasion and survival of UPEC in the prostate cells, and inhibit LPS-induced inflammatory responses through the JAK/STAT1 pathway have also been indicated. Our results demonstrated testosterone not only suppressed the invasion and colonization of UPEC, but also inhibited the expression of pro-inflammatory IL-1β, IL-6 and IL-8 cytokines expression induced by UPEC in a dose-dependent manner. We found the effective dose of testosterone to suppress UPEC infect prostate cells may be appropriate under 40μg/ml. Our data also revealed 20μg/ml testosterone treated PZ-HPV-7 cells significantly suppressed the LPS-induced JAK/STAT1 pathway and inflammatory responses, and reached to maximal effects at 40μg/ml treatment. These results indicate that testosterone plays an anti-inflammatory role in LPS-induced prostate cell inflammation by down-regulating JAK/STAT1 signaling pathway. Interestingly, the JAK inhibitor and testosterone for 24hr pretreatment rather markedly induced the colonization of UPEC in the PZ-HPV-7 cells. Based on the above data, the suppression of UPEC colonization in the prostate cells by testosterone seems to be unrelated with JAK/STAT signaling pathway, whereas the JAK may involve into the UPEC infection. Summing up these data, our findings have demonstrated the suppressive effects of testosterone on the invasion and survival of UPEC and induced inflammation in prostate epithelial cells. These findings indicate the action mechanism of testosterone as an anti-inflammatory mediator in the prostate cells is regulated through JAK/STAT1 signaling pathway, may be beneficial in treating prostate inflammation. Altogether, this study has provided the possibility that using testosterone in the prevention and clinical treatment of prostatitis is a new direction.

Partial Text

Uropathogenic Escherichia coli (UPEC) is the most common causative microorganism of urinary tract infection and accounts for the majority of acute and chronic bacterial prostatitis. With the expression of multiple virulence factors, such as fimbriae, lipopolysaccharide (LPS), and toxins, UPEC can trigger a series of host inflammatory responses, including cytokine production, neutrophil influx, and the exfoliation of uroepithelial cells [1]. Moreover, a substantial body of evidence has demonstrated that UPEC is capable of invading the epithelial cells of urinary bladder and forming a biofilm-like intracellular bacterial community [2]. This mechanism enables UPEC to evade host defense and antibiotic therapy and serves as a reservoir for recurrent or chronic infection. The intracellular colonization of UPEC has also been also demonstrated in prostate epithelial cells [3]. A recent study demonstrated the ability of as many as 58 UPEC strains to adhere to and invade normal human prostate cells with high efficiency [4]. These strains are capable of activating mitogen-activated protein kinase and NF-κB signaling pathways in the prostate RWPE-1 cell line, inducing release of proinflammatory cytokines, IL-6 and IL-8. [4]. An animal study demonstrated a high prevalence of UPEC persistence in the prostate tissue after 14 day of bacterial infection, suggesting UPEC colonization could be a frequent sequela of acute prostatitis [5].

Uropathogenic Escherichia coli (UPEC) causes frequent bacterial prostatitis by refluxing the infected urine into prostatic ducts, which results in an ascending urethral infection [32, 33]. However most urinary tract infection-related studies focus on bladder cells, and studies regarding the ability of UPEC to invade, replicate, and persist in normal prostate epithelial cell are limited [3]. In this study, we established a normal prostate cell model for evaluating the ability of UPEC to invade the urothelium and colonize intercellular bacterial communities in vitro. Using this model, we demonstrated that testosterone effectively suppresses the invasion and survival of UPEC in prostate cells. In addition, testosterone-mediated inhibition of LPS-induced inflammatory responses through the JAK/STAT1 pathway has also been indicated.