Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury.
Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.
Department of Hematology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan. yuji0516@med.kindai.ac.jp
Yuji
Y
Nozaki
Koji
K
Kinoshita
Tomohiro
T
Yano
Kayo
K
Asato
Toshihiko
T
Shiga
Shoichi
S
Hino
Kaoru
K
Niki
Yasuaki
Y
Nagare
Kazuya
K
Kishimoto
Hideki
H
Shimazu
Masanori
M
Funauchi
Itaru
I
Matsumura
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D017209:Apoptosis; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002945:Cisplatin / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000072596:Hepatitis A Virus Cellular Receptor 1; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D020382:Interleukin-18 / Q000097:blood / Q000652:urine; D053727:Interleukin-18 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D019138:Antibodies, Blocking; D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008565:Membrane Proteins; D012333:RNA, Messenger; C498144:Rela protein, mouse; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002945:Cisplatin