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 Th1 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, DTH-mediated crescentic glomerulonephritis induced by planting an Ag in glomeruli of sensitized mice as well as in cutaneous DTH. Sensitized genetically normal (IL-12(+/+)) mice developed proteinuria and crescentic glomerulonephritis with a glomerular influx of DTH effectors (CD4(+) T cells, macrophages, and fibrin deposition) in response to the planted glomerular Ag. IL-12p40-deficient (IL-12(-/-)) mice showed significant reductions in crescent formation, proteinuria, and glomerular DTH effectors. Administration of IL-18 to IL-12(-/-) mice restored the development of histological (including effectors of DTH) and functional glomerular injury in IL-12(-/-) mice to levels 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 intradermal 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 cutaneous DTH, demonstrating the synergistic effects of IL-18 and IL-12 in DTH responses. 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 IFN-gamma, GM-CSF, or TNF-alpha production.
Kitching
A R
AR
Centre for Inflammatory Diseases, Department of Medicine Monash Medical Centre, Monash University, Clayton, Victoria, Australia. richard.kitching@med.monash.edu.au
Tipping
P G
PG
Kurimoto
M
M
Holdsworth
S R
SR
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D007111:Immunity, Cellular / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011994:Recombinant Proteins / Q000008:administration & dosage; D012882:Skin Tests; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007074:Immunoglobulin G; D020382:Interleukin-18; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12