Intrinsic expression of Th2 cytokines in urothelium of congenital ureteropelvic junction obstruction

Abstract

The cytokine-producing ability of urothelium, a urinary tract barrier between urine and underlying connective tissue, may exacerbate the pathogenesis of congenital ureteropelvic junction obstruction (UPJ-O) disease. A role for urothelium in human urinary tract obstruction has rarely been described. In this study, we investigated the immunopathologic characteristics of, and cytokine production by, urothelium in children with congenital UPJ-O. Twenty-four children with congenital UPJ-O who had received pyeloplasty were enrolled. Morphologic abnormalities and pathologic and inflammatory changes of UPJ-O segments were studied. Expression of cytokines and chemokines in urothelium was investigated and compared with control tissue by immunohistochemistry (IHC), in situ hybridization (ISH), and urinary enzyme-linked immunosorbent assay (ELISA). Atypical or simple hyperplasia of the urothelium with evidence of Ki67 over-expression was found frequently in UPJ-O. There were variable degrees of inflammatory cell and eosinophil infiltration. Augmented expression of IL-5 and eotaxin detected by IHC and ISH, and enhanced degranulation of tissue mast cells were observed in the urothelium of UPJ-O segments. IL-4, IFN-gamma, and TNF-alpha were undetectable. Significantly higher levels of urinary IL-5, IFN-gamma, and eotaxin were detected in urine collected from the obstructed kidney. Among these, high urinary IL5 and/or IFN-gamma levels were associated with more severe obstructive uropathy (P < 0.05). Urothelium, like intestinal and respiratory epithelia, plays an active role in immunoregulation and may contribute to exacerbation of the pathogenesis of congenital UPJ-O. Many eosinophil-associated disease cytokines, which can lead to the degranulation of mast cells, are predominant regulators in UPJ-O urothelium.