Akin to the gastrointestinal and pulmonary tracts, dysregulated epithelial signaling in the genitourinary system may lead to marked organ dysfunction. The expression of multiple TLRs within the urinary epithelium has now been established, suggesting the possibility that TLR signaling may regulate the interaction of the urinary epithelium with potential pathogens (see Table 3 ). TLR signaling within urinary tract epithelial cells leads to pro-inflammatory signaling in response to uropathogenic E. coli (UPEC) and LPS (109, 110) . Furthermore, modulation of uroepithelial inflamma-tion may be mediated by sensitization of the uroepithelium through regulation of epithelial TLR expression in response to infection or injury. An increase in TLR4 expression in the urinary epithelium has been observed during systemic sepsis in a murine model of cecal ligation and puncture (111) , and an increase in renal epithelial TLR2 and TLR4 expression has been observed in a murine model of local renal inflammation induced by ischemia (112) . Further demonstrating a role for TLR activation in uroepithelial inflammation, TLR4 mutant C3H/Hej mice failed to clear uropathogenic E. coli (UPEC) and showed reduced inflammatory mediator production compared with wild-type controls (109) . TLR4 mutant C3H/Hej mice were resistant to LPSinduced renal failure, had less renal neutrophilic infiltrate, and less renal cell apoptosis compared with wild-type controls (113) . In addition to TLR4, other TLRs may participate in the development of uroepithelial inflammation. For instance, TLR5-deficient mice were found to be more susceptible to experimental UPEC urinary tract infection compared with wild-type counterparts (16) , while mice with null mutations in TLR11, which is normally found to be strongly expressed in the bladder and kidney epithelium, developed markedly less severe kidney inflammation compared with wild-type counterparts (114) . TLR2-deficient mice were protected from tubular injury and renal function deterioration in a model of kidney ischemiareperfusion (115) . The clinical significance of a role for TLR signaling in the pathogenesis of genitourinary inflammation is found in clinical studies in which the incidence of acute rejection after kidney transplantation is reduced in patients who received a graft heterozygous for either the TLR4 Asp299Gly or Thr399Ile polymorphism compared with grafts without these mutations (189) , although conflicting results have been reported (190) . Taken together, these studies suggest an important role for TLR signaling in the development of urinary tract inflammation in a variety of models.