A Synthetic Peptide 2Abz(23)S(29) Reduces Bacterial Titer and Induces Pro-Inflammatory Cytokines in a Murine Model of Urinary Tract Infection

INTRODUCTION: A urinary tract infection (UTI), which is often caused by uropathogenic E. coli (UPEC) strains, affects many people worldwide annually. UPEC causes the production of pro-inflammatory cytokines by the bladder epithelial cells; however, it has been proven that the UPEC can inhibit the early activation of the innate immune system. METHODS: This study aimed to examine the antibacterial and immunomodulatory effects of different doses of truncated alpha-defensins (human neutrophil peptide (HNP)-1) analog 2Abz(23)S(29) on the mouse UTI model. Experimentally uropathogenic E. coli CFT073-infected mice were treated with low-dose 2Abz(23)S(29) (250µg/mL), high-dose 2Abz(23)S(29) (750µg/mL), ciprofloxacin (cip) (800µg/mL), or high-dose 2Abz(23)S(29)plus cip once a day 24 h post-infection. The 2Abz(23)S(29) and cip treatment were given for two consecutive days. RESULTS: The in vivo results showed that fewer UPEC were recovered from the bladders of mice treated transurethrally with 2Abz(23)S(29). Moreover, low-dose 2Abz(23)S(29) significantly decreased the level of the interleukin-6 (IL-6), whereas high-dose 2Abz(23)S(29) increased pro-inflammatory cytokines including IL-6, macrophage inflammatory protein/2 (MIP/2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in infected bladders of mice. Besides, the levels of cytokines IL-6 and MIP/2 in infected mice treated with a combination of high-dose 2Abz(23)S(29) and cip were significantly higher than the untreated mice. In contrast, CFT073-infected mice treated with a combination of high-dose 2Abz(23)S(29) and cip showed no changes in cytokines TNF-α and IL-1β levels, indicating that ciprofloxacin may play an anti-inflammatory role. CONCLUSION: Collectively, apart from the direct antibacterial role of 2Abz(23)S(29), our data illustrated that 2Abz(23)S(29) modulates pro-inflammatory cytokine production of bladder in a dose-dependent manner, which has implications for the development of new anti-infective agents.