title: The pathological role of IL-18Rα in renal ischemia/reperfusion injury.
abstract: Interleukin (IL)-18 is a proinflammatory cytokine produced by leukocytes and parenchymal cells (eg, tubular epithelial cells (TECs), mesangial cells, and podocytes). IL-18 receptor (IL-18R) is expressed on these cells in the kidney during ischemia/reperfusion injury (IRI), but its role in this injury is unknown. Fas/Fas ligand (FasL) is also involved in the pathogenesis of renal IRI via tubular apoptosis. In addition, IL-18 enhances the expression of FasL on TECs, but the mechanism underlying this enhancement is not known. Here we used IL-18Rα-deficient mice to explore the pathological role of IL-18Rα in renal IRI. We found that compared to wild-type (WT) mice with renal IRI as an acute kidney injury (AKI), the IL-18Rα-deficient mice demonstrated decreased renal function (as represented by blood urea nitrogen), tubular damage, an increased accumulation of leukocytes (CD4+ T cells, neutrophils, and macrophages), upregulated early AKI biomarkers (ie, urinary kidney injury molecule-1 levels), and increased mRNA expressions of proinflammatory cytokines (IL-1β, IL-12p40, and IL-18) and chemokines (intercellular adhesion molecule-1 and CCL2/monocyte chemoattractant protein-1). The mRNA expression of FasL in the kidney was increased in the IL-18Rα-deficient mice compared to the WT mice. The adoptive transfer of splenocytes by WT mice led to decreased renal IRI compared to the IL-18Rα-deficient mice. In vitro, the mRNA expression of FasL on TECs was promoted in the presence of recombinant IL-18. These data reveal that IL-18Rα has an anti-inflammatory effect in IRI-induced AKI. Above all, IL-18 enhanced the inflammatory mechanisms and the apoptosis of TECs through the Fas/FasL pathway by blocking IL-18Rα.
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hino
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Niki
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimazu
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kishimoto
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Funauch
authors.affiliation: Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D053724:Receptors, Interleukin-18