| Research Abstract |
IL-18 was discovered in 1995 as an IFN-γ-inducing factor in this institute. It is a cytokine with pleiotropic actions and now under vigorous investigation. IL-18 induces iNOS, COX-2, Fas ligand, and not only Th1 cytokines IFN-γ but Th2 cytokine such as IL-4, IL-5, and IL-13. The actions of IL-18 was reviewed by us in Ann.Rev.Immunol. (Annu.Rev.Immunol. 2001, 19 ; 423-474). IL-18 is profoundly involved in inflammatory reactions. And in the present study, we have shown that IL-18 in combination with IL-12 causes multiple organ dysfunction when administered to mice. When IL-12 and IL-18 were separately given to mice, they caused apparently no pathological changes, but when given in combination, they caused severe erosion in the intestine, atrophy in the thymus, fatty degeneration in the liver, and death in a few days. These cytokines failed to cause these pathological changes in IFN-γ-deficient mice, and induced milder changes in iNOS deficient mice. The change first appeared in the gland tissues and mumerous apoptotic cells were observed in the lacrimal gland. The administration of IL-12 and IL-18 failed to cause apoptotic changes in iNOS deficient mice. Various caspase inhibitors diminished the histological changes in the lacrimal gland. Thus, it was shown that IL-18 together with IL-12 is involved in the tissue damage through strong induction of IFN-γ. Moreover the down stream product, nitric oxide and reactive oxygen species were suggested to be directly responsible for the tissue damages. Thus IL-18 and IL-12 activate the destructive pathway by inducing IFN-γ, but recent studies revealed that IL-18 induces Th2 or anti-inflammatory cytokines such as IL-4, IL-5, and IL-13 in the absence of IL-12. Therefore, IL-18 may be involved also in the regulation of destructive pathway by inhibiting Th1 cytokines through induction of Th2 cytokines. Much remains to be clarified for this attractive cytokine.
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