Macrophage-derived interleukin-18 in experimental renal allograft rejection.
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.


CONCLUSIONS
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.
Wyburn
Kate
K
Transplantation Laboratory, Royal Prince Alfred Hospital, University of Sydney, NSW 2006, Australia. kwyburn@med.usyd.edu.au
Wu
Huiling
H
Yin
Jianlin
J
Jose
Matthew
M
Eris
Josette
J
Chadban
Steven
S
D000208:Acute Disease; D000818:Animals; D006084:Graft Rejection / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew
D016209:Interleukin-8