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Macrophage-derived interleukin-18 in experimental renal allograft rejection


Wyburn, K and Wu, H and Jose, MD and Eris, J and Chadban, S, Macrophage-derived interleukin-18 in experimental renal allograft rejection, Nephrology dialysis transplantation, 20, (4) pp. 699-706. ISSN 1460-2385 (2005) [Refereed Article]

Copyright Statement

Copyright 2005 The Author

DOI: doi:10.1093/ndt/gfh712


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-gamma 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-gamma 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.

Item Details

Item Type:Refereed Article
Keywords:allograft rejection
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Nephrology and urology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Jose, MD (Professor Matthew Jose)
ID Code:90575
Year Published:2005
Web of Science® Times Cited:35
Deposited By:Medicine
Deposited On:2014-04-10
Last Modified:2014-11-06

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