Alterations in renal interleukin-1 production during kidney transplant rejection in the rat. The effects of high-dose methylprednisolone.

To characterize the role of interleukin-1 in renal allograft rejection, we examined the temporal relationship of IL-1 production to changes in renal function and histology in a rat kidney transplantation model. In rat renal allografts, both glomerular filtration rate and renal plasma flow (RPF) fell progressively from days 4 through 6 following transplantation. The reduction in allograft function was accompanied by histologic changes consistent with rejection and enhanced steady-state levels of IL-1 beta mRNA measured by Northern blot. This increase in IL-1 beta mRNA levels was associated with a forty-fold increase in IL-1 bioactivity in eluates of kidney allografts compared with isografts. In rejecting allografts, these changes also coincided with increased production of thromboxane B2 (TxB2) by the graft. To attempt to modify IL-1 production in the transplanted kidney, a separate group of animals with renal allografts were treated with 80 mg/kg/day of methylprednisolone for 6 days. GFR in MP-treated animals was significantly preserved compared with vehicle-treated animals. However, similar histologic manifestations of rejection were found in both groups. Although IL-1 beta mRNA levels in the kidney were not changed with MP treatment, renal IL-1 bioactivity was reduced four-fold in animals that received MP compared with controls. Thus, IL-1 beta gene expression and IL-1 protein production are stimulated in rejecting kidney transplants. MP administration improves allograft function and inhibits IL-1 production, apparently at a post-transcriptional level. We hypothesize that overproduction of IL-1 during kidney transplant rejection may promote allograft dysfunction and injury. Some of the beneficial effects of corticosteroids in acute rejection may be mediated through inhibition of IL-1 release within the allograft.

Duke Scholars

Author Thomas Myron Coffman Medicine, Nephrology