IL-18 has IL-12-independent effects in delayed-type hypersensitivity: Studies in cell-mediated crescentic glomerulonephritis

IL-18 (formerly known as IFN-gamma-inducing factor) enhances Thl responses via effects that are thought to be dependent on and synergistic with IL-12, The potential for IL-18 to exert IL-12-independent effects in delayed-type hypersensitivity (DTH) responses was studied in a model of Th1-directed, D TH-mediated crescentic glomerulonephritis induced by planting an Ag in glom eruli of sensitized mice as well as in cutaneous DTH, Sensitized geneticall y normal (IL-12(+/+)) mice developed proteinuria and crescentic glomerulone phritis with a glomerular influx of DTH effecters (CD4(+) T cells, macropha ges, and fibrin deposition) in response to the planted glomerular Ag, IL-12 p40-deficient (IL-12(-/-)) mice showed significant reductions in crescent f ormation, proteinuria, and glomerular DTH effecters. Administration of IL-1 8 to IL-12(-/-) mice restored the development of histological (including ef fecters of DTH) and functional glomerular injury in IL-12(-/-) mice to leve ls equivalent to those in IL-12(+/+) mice, IL-18 administration to IL-12(-/ -) mice increased glomerular ICAM-1 protein expression, but did not restore Ag-stimulated splenocyte IFN-gamma, GM-CSF, IL-2, or TNF-alpha production. Sensitized IL-12(+/+) mice also developed cutaneous DTH following intrader mal challenge with the nephritogenic Ag, Cutaneous DTH was inhibited in IL- 12(-/-) mice, but was restored by administration of IL-18, IL-12(+/+) mice given IL-18 developed augmented injury, with enhanced glomerular and cutane ous DTH, demonstrating the synergistic effects of IL-18 and IL-12 in DTH re sponses. These studies demonstrate that even in the absence of IL-12, IL-18 can induce in vivo DTH responses and up-regulate ICAM-1 without inducing I FN-gamma, GM-CSF, or TNF-alpha production.