IL-18 Contributes to Renal Damage after Ischemia-Reperfusion : Journal of the American Society of Nephrology (original) (raw)

BASIC RESEARCH

Wu, Huiling*; Craft, Melissa L.*; Wang, Peng*; Wyburn, Kate R.*; Chen, Gang*; Ma, Jin*; Hambly, Brett†; Chadban, Steven J.*

*Collaborative Transplant Research Group, Renal Medicine, Royal Prince Alfred Hospital and Bosch Institute, Faculty of Medicine, University of Sydney, and †Pathology Discipline, Bosch Institute, School of Medical Science, University of Sydney, Sydney, Australia

Correspondence: Dr. Huiling Wu, Collaborative Transplant Research Group, Room W607, Blackburn Building D06, University of Sydney, NSW 2006, Australia. Phone: +612-9351-2898; Fax: +612-9351-8771; E-mail: [email protected]

Accepted July 18, 2008

Received February 12, 2008

Abstract

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.