IL-18 contributes to renal damage after ischemia-reperfusion.
IL-18 is a proinflammatory cytokine produced by macrophages and other cell types present in the kidney during ischemia-reperfusion injury (IRI), but its role in this injury is unknown. Here, compared with wild-type mice, IL-18(-/-) mice subjected to kidney IRI demonstrated better kidney function, less tubular damage, reduced accumulation of neutrophils and macrophages, and decreased expression of proinflammatory molecules that are downstream of IL-18. For determination of the relative contributions of leukocytes and parenchymal cells to IL-18 production and subsequent kidney damage during IRI, bone marrow-chimeric mice were generated. Wild-type mice engrafted with IL-18(-/-) hemopoietic cells showed less kidney dysfunction and tubular damage than IL-18(-/-) mice engrafted with wild-type bone marrow. In vitro, macrophages produced IL-18 mRNA and protein in response to ischemia. These data suggest bone marrow-derived cells are the key contributors to IL-18-mediated effects of renal IRI. Finally, similar to IL-18(-/-) mice, pretreatment of wild-type mice with IL-18-binding protein was renoprotective in this model of IRI. In conclusion, IL-18, derived primarily from cells of bone marrow origin, contributes to the renal damage observed during IRI. IL-18-binding protein may have potential as a renoprotective therapy.
Wu
Huiling
H
Collaborative Transplant Research Group, Renal Medicine, Royal Prince Alfred Hospital and Bosch Institute, Faculty of Medicine, University of Sydney, Sydney, Australia. huilingw@med.usyd.edu.au
Craft
Melissa L
ML
Wang
Peng
P
Wyburn
Kate R
KR
Chen
Gang
G
Ma
Jin
J
Hambly
Brett
B
Chadban
Steven J
SJ
D000818:Animals; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007249:Inflammation; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D007511:Ischemia; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*
D020382:Interleukin-18; D012333:RNA, Messenger