Insulin Downregulated the Infection of Uropathogenic Escherichia coli (UPEC) in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway.

Chen-Hsun Ho,Shih-Ping Liu,Kai-Yi Tzou,Chia-Chang Wu,Po-Ching Cheng,Chia-Kwung Fan

doi:10.3390/microorganisms9122421

Abstract

Diabetic individuals have a higher incidence of urinary tract infection (UTI) than non-diabetic individuals, and also require longer treatment. We evaluated the effects of insulin pretreatment on the regulation of JAK/STAT transduction pathways in UPEC-infected bladder cells in a high-glucose environment. A bladder cell model with GFP-UPEC and fluorescent-labeled TLR4, STAT1, STAT3, and insulin receptor antibodies, was used to evaluate the relationship between insulin receptor signaling, TLR-4-mediated, and JAK/STAT-dependent pathways. Pretreatment with 20 and 40 µg/mL insulin for 24 h significantly and dose-dependently reduced UPEC infection in SV-HUC-1 cells. Additionally, the expression levels of STAT1 and STAT3 were downregulated in a dose-dependent manner. However, insulin receptor (IR) expression was not affected by insulin pretreatment. Our results showed that insulin-mediated reduction of UPEC infection in a high-glucose environment was not only due to the downregulation of JAK1/2 and phosphorylated STAT-1/3, but also because of the decreased expression of TLR-4 proteins and pro-inflammatory IL-6. Here, we demonstrated that insulin reduced not only UPEC infection in bladder epithelial cells, but also inhibited the JAK/STAT transduction pathway during infection in a high-glucose environment. This study provides evidence to support the use of insulin in the treatment of UPEC infection in patients with type 2 diabetes (T2D).

Highlights

Introductionurinary tract infection (UTI) is an infection in any part of the urinary system, including the kidneys, ureters, bladder and urethra, especially the lower urinary tract, the bladder and the urethra
(A) The frequency of GFP, insulin receptor (IR), STAT1, and STAT3 expression in uninfected and UPEC-infected bladder cells with or without different concentrations of insulin (10, 20, and 40 μg/mL), and 15 mM glucose pretreatment for 24 h is shown as a histogram, and the results shown are representative of typical results
STAT1 and STAT3 phosphorylation in these cells determine their antagonistic functions in regulating growth arrest and inflammation [39]

Summary

Introduction

UTI is an infection in any part of the urinary system, including the kidneys, ureters, bladder and urethra, especially the lower urinary tract, the bladder and the urethra. Some studies point out that 1/3 of women will develop UTI during their lifetime [1,2]. Most cases of cystitis are caused by UPEC [3]. 76.7% of the bacteria in female patients with urinary tract infections are E. coli [4]. Known as a kind of UTI, usually occurs when bacteria from outside enter the urethra and begin to proliferate, often accompanied by frequent urination, urgency, burning or pain during

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Conclusion