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(PP)
A NEWLY IDENTIFIED ROLE FOR INTERLEUKIN-22 IN BLADDER IMMUNITY
Michael HSIEH
1
and Jared HONEYCUTT
2
1) Children's National Health System, Urology, Washington, USA - 2) Stanford University, Urology, Stanford, USA
PURPOSE
Bacterial and parasitic urinary tract infections(UTI) plague many children but our understanding of immunity to these
pathogens remains poor. Recent data indicates that during infection of other epithelial organs, interleukin-22(IL-22) is
crucial for epithelial immunity. We hypothesized that IL-22 would prove crucial during UTI.
MATERIAL AND METHODS
IL-22-null(KO) and wild type(wt) mice underwent bladder wall injection with S. haematobium eggs(eggs) or
transurethral uropathogenic E. coli(UTI89) infection. 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
Bladder levels of IL-22 and its soluble binding protein(IL-22BP) increased after egg exposure. Genes typically induced by
IL-22 were expressed at higher levels after egg injection. IL-22 stimulation of bladder tissue and the MBT-2 bladder
cancer cell line induce expression of antimicrobial proteins. IL-22 receptor-α1 expression was detectable in the
urothelium by immunofluorescence and qPCR.
Egg injection into IL-22-KO vs wt mice induced differential expression of genes related to transferase activity and
epithelial cell development. Uroplakin gene expression was downregulated in egg-injected, IL-22-KO mice vs. wt
counterparts. These decreases in uroplakin expression suggest that, as in the gut, IL-22 replenishes epithelia during
infection-related injury.
IL-22-KO and wt mice were transurethrally infected with UTI89. FimH is an adhesin used by type I piliated bacteria like
UTI89 to bind to the uroplakins of mature urothelial cells, permitting urothelial colonization during UTI. IL-22-KO mice
had less urine, bladder, and kidney bacteria. Giving stabilized IL-22 cytokine (IL-22-Fc) to UTI89-infected mice led to
higher kidney bacterial counts and increased morbidity.
CONCLUSIONS
Our data underscore IL-22's importance in urinary tract immunity, and its interference with clearance of bacteria from
the urinary tract, potentially through its role in maintenance of mature urothelium.