NDT Advance Access originally published online on February 16, 2005
Nephrology Dialysis Transplantation 2005 20(4):699-706; doi:10.1093/ndt/gfh712
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Macrophage-derived interleukin-18 in experimental renal allograft rejection
1 Transplantation Laboratory, Royal Prince Alfred Hospital and The University of Sydney, NSW, Australia and 2 Department of Nephrology, Monash Medical Centre, Victoria, Australia
Correspondence and offprint reprints to: Dr Kate Wyburn, Transplantation Laboratory, Blackburn Building w607, University of Sydney, NSW 2006, Australia. Email: kwyburn{at}med.usyd.edu.au
Background. Interleukin 18 (IL-18) is primarily a macrophage-derived, pro-inflammatory cytokine. As macrophages can act as effector cells in acute rejection, we examined the role of IL-18 in a rat model of acute renal allograft rejection.
Methods. Life-sustaining orthotopic DA to Lewis allograft and Lewis-Lewis isograft kidney transplants were performed. In the same model, macrophage-depleted animals, achieved with liposomal-clodronate therapy, were also studied. Macrophage (ED1+) accumulation and IL-18 expression was assessed by immunohistochemistry. CD11b+ cells (macrophages) were isolated from kidney and spleen by micro beads. Real-time PCR was used to assess IL-18 and INF-
mRNA expression in tissue and cell isolates.
Results. Allografts, but not isografts, developed severe tubulo-interstitial damage and increased serum creatinine by day 5 (P<0.001). Immunohistochemistry revealed a greater ED1+ cell accumulation in day 5 allografts compared with isografts (P<0.001). IL-18 mRNA expression was increased 3-fold in allografts compared to isografts (P<0.001). Accordingly, IL-18 protein was increased in allografts (P<0.001), and was predominantly expressed by ED1+ macrophages. CD11b+ macrophages isolated from allografts had a 6-fold upregulation of IL-18 mRNA expression compared to isograft macrophages (P<0.001). Macrophage depletion resulted in a marked attenuation of allograft rejection, ED1+ and IL-18+ cells were significantly reduced (P<0.05) as was IL-18 mRNA expression (29.28±2.85 vs 62.48±3.05, P<0.001). INF- mRNA expression (P<0.01) and iNOS (P<0.001) production were also significantly reduced in the macrophage-depleted animals.
Conclusion. This study demonstrates that IL-18 is significantly increased during acute rejection and is principally produced by intra-graft macrophages. We hypothesize that IL-18 upregulation may be an important macrophage effector mechanism during the acute rejection process.
Keywords: acute allograft rejection; interleukin-18; kidney transplantation; macrophages
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