Pathological roles of interleukin-18 in graft-versus-host disease and rejection of grafts

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Bone marrow transplantation is an effective therapy for hematopoietic malignancy, such as leukemia, and immunodeficient diseases. However, immunological reactions based on the difference of major histocompatibility complex occasionally cause various pathological changes in recipients. Acute graft-versus-host disease (aGVHD), fatal side effects of bone marrow transplantation, has been shown to be accompanied with elevation of serum levels of interleukin (IL) -18. IL-18 is a proinflammatory cytokine and is produced as biologically inactive precursor. After appropriate stimulation, precursor IL-18 is cleaved into mature IL-18 by caspase-1 or caspase-1-like enzyme, leading to release of mature IL-18. Here, we investigated the mechanism underlying the accumulation of IL-18 in aGVHD in mice. Lethally irradiated recipients transplanted with H-2 disparate donor splenocytes confessed aGVHD and contained markedly elevated serum levels of IL-18. While recipients transplanted with gld/gld spleen cells, that lack functional Fas ligand (FasL), contained only normal ranges of IL-18, indicating FasL-mediated IL-18 release in aGVHD.The wild type hosts engrafted with caspase-1-deficient cells revealed marked increases of IL-18 level similar to those engrafted with wild type cells, while caspase-1-deficient recipients engrafted with wild type cells showed only slight elevation of serum IL-18, indicating that IL-18 elevation is derived from host cells in a caspase-1-dependent manner. These results suggested FasL-mediated caspase-1-dependent IL-18 secretion in aGVHD in mice.