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A Newly Identified Role for Interleukin-22 in Bladder Immunity
Jared Honeycutt, Stanford, CA, Michael Hsieh*, Washington, DC

INTRODUCTION AND OBJECTIVES: Bacterial and parasitic urinary tract infections(UTI) plague many children and yet our understanding of immunity to these pathogens remains poor. Recent data indicates that during infection of other epithelial organs, interleukin-22(IL-22) is a key cytokine for epithelial immunity. We hypothesized that IL-22 would prove crucial during UTI.

METHODS: IL-22-null (KO) and wild type (wt) mice underwent bladder wall injection with S. haematobium eggs or transurethral infection with type 1 piliated uropathogenic E. coli UTI89. Bladder RNA and protein expression was analyzed by qPCR and microarrays and immunofluorescence, and infiltrating cells characterized by flow cytometry. Urine, bladder, and kidney cfu were measured in UTI89-infected mice.

RESULTS: Levels of IL-22 and its soluble binding protein, IL-22BP, were increased in the bladder after exposure to S. haematobium eggs. Genes typically induced by IL-22 (CXCL2, REG3G[antimicrobial defense protein]], S100A8, S100A9, and Areg) were expressed at higher levels after S. haematobium egg injection. IL-22 stimulation of bladder tissue and the MBT-2 bladder cancer cell line induce expression of the antimicrobial proteins REG3B and REG3G. IL-22 receptor α1 expression was detectable in the urothelium by immunofluorescence and qPCR. Injection of S. haematobium eggs into IL-22-KO vs wt mice resulted in differential expression of genes related to glutathione transferase activity, transferase activity(transferring alkyl or aryl groups), and epithelial cell development. Numerous genes for the uroplakins were downregulated in egg-injected, IL-22-KO mice relative to their wt counterparts. These decreases in uroplakin expression suggest that, as in the gut, IL22 is important for replenishing the epithelial lining during infection-related injury. IL-22-KO and wild-type littermate mice were transurethrally infected with UTI89. FimH is a principal adhesin used by type I piliated bacteria like UTI89 to bind to the uroplakin receptor complex of mature urothelial cells, permitting colonization of the urothelium during UTI. IL-22-KO mice had lower bacterial counts in their urine, bladder, and kidneys. Giving stabilized IL-22 cytokine (IL-22-Fc) to UTI89-infected mice led to higher kidney bacterial counts and increased morbidity.

CONCLUSIONS: Our data suggest that IL-22 is indeed important in urinary tract immunity, and may interfere with clearance of bacteria from the urinary tract, potentially through its role in maintenance of mature urothelium.

Source of Funding: DK 087895

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