title: Interleukin-18 affects local cytokine expression but does not impact on the development of kidney allograft rejection.
abstract: Interleukin-18 is predominantly a macrophage-derived cytokine with a key role in inflammation and cell-mediated immunity. Having previously demonstrated IL-18 upregulation in a rat model of kidney rejection, here we examined IL-18 in a fully MHC-mismatched murine model of acute kidney rejection using IL-18-deficient recipients (IL-18-/-) and animals administered neutralizing IL-18 binding protein (IL-18BP). Gene expression of IL-18 and its receptor were significantly upregulated in allografts compared to isografts, as was the cellular infiltrate (T cells and macrophages) (p < 0.001). Allografts developed kidney dysfunction (p < 0.05) and tubulitis (p < 0.01) not observed in controls. There was a significant reduction in gene expression of IL-18 downstream pro-inflammatory molecules (iNOS, TNFalpha and IFNgamma) in IL-18-/- recipients (p < 0.01), and IL-18BP-treated animals. The CD4+ infiltrate and IL-4 mRNA expression was greater in the IL-18-/- recipients than wild-type (WT) allografts and IL-18BP-treated animals (p < 0.05), suggesting a Th2-bias which was supported by IFNgamma and IL-4 ELISPOT data and an increased eosinophil accumulation (p < 0.001). Neither IL-18 deficiency nor neutralization prevented renal dysfunction or tubulitis. This study demonstrates increased production of IL-18 in murine kidney allograft rejection and provides evidence that IL-18-induced pathways of inflammation are active. However, neither IL-18 deficiency nor neutralization was protective against the development of allograft rejection.
authors.affiliation: Collaborative Transplant Laboratory, The University of Sydney & Royal Prince Alfred Hospital, Sydney, Australia. kwyburn@med.usyd.edu.au
authors.forename: K
authors.initials: K
authors.lastname: Wyburn
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.forename: J
authors.initials: J
authors.lastname: Eris
authors.forename: S
authors.initials: S
authors.lastname: Chadban
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics*; D018076:DNA, Complementary / Q000302:isolation & purification; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000302:isolation & purification; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D020382:Interleukin-18; D015847:Interleukin-4; D012313:RNA