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It has been well recognized that the promoter polymorphisms of interleukin-18 (IL-18) influence the level of cytokine expression. In our previously published data, we showed constitutive IL-18 expression in the epithelium of renal distal tubules in patients after kidney transplantation and significantly elevated IL-18 expression during acute rejection. In this study, we evaluated the clinical significance of two functional promoter polymorphisms of the IL-18 gene at positions -607 A/C (rs1946518) and -137 C/G (rs187238) in patients after kidney transplantation and looked for associations with the onset of graft function and the incidence of rejection episodes. Promoter polymorphisms in 124 patients and 103 unrelated controls were evaluated by sequence-specific primer polymerase chain reaction and the allele, genotype and haplotype frequencies were statistically correlated. We found a statistically different distribution of the allele frequency of -607 A/C polymorphism between patients with immediate or delayed onset of kidney graft function. Data showed that the C allele, which contributes to higher IL-18 expression, is more frequent in patients with delayed onset of function (P = 0.03, odds ratio = 1.93; 95% confidence interval = 1.15-3.25). A/C single nucleotide polymorphisms of the IL-18 promoter at position -607 may influence the onset of early kidney allograft function.

IL-18 is a multifunctional cytokine that augments both innate and acquired immunity and potentiates Th1 and Th2 reactions. We studied the expression of IL-18 receptor (IL-18R) on renal and respiratory epithelial cell lines. Both cell lines upregulated IL-18R mRNA and IL-18R membrane expression in response to TNF alpha and other proinflammatory cytokines. The function of IL-18R was confirmed by induction of IL-8 release from epithelial cells in response to recombinant IL-18. Epithelial cells may represent an important target for IL-18, mainly under inflammatory conditions associated with TNF alpha release.