Pathophysiological roles of interleukin-18 in inflammatory liver diseases.
Innate immune response to microbes sometimes determines the nature of the following specific immune response. Kupffer cells, a potent constituent of innate immunity, play a key role in developing the type 1 immune response by interleukin (IL)-12 production. Furthermore, Kupffer cells have the potential to induce liver injury by production of IL-18. Propionibacterium acnes-primed lipopolysaccharide (LPS)-challenged liver injury is the prototype of IL-18-induced tissue injury, in which IL-18 acts on natural killer cells to increase Fas ligand (FasL) that causes liver injury by induction of Fas-dependent hepatocyte apoptosis. LPS induces IL-18 secretion from Kupffer cells in a caspase-1-dependent manner. Indeed, caspase-1-deficient mice are resistant to P. acnes and LPS-induced liver injury. However, administration of soluble FasL induces acute liver injury in P. acnes-primed caspase-1-deficient mice but does not do so in IL-18-deficient mice, indicating that IL-18 release in a caspase-1-independent fashion is essential for this liver injury. Therefore, a positive feedback loop between FasL and IL-18 plays an important role in the pathogenesis of endotoxin-induced liver injury.
Tsutsui
H
H
Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan.
Matsui
K
K
Okamura
H
H
Nakanishi
K
K
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D020170:Caspase 1 / Q000502:physiology; D002522:Chlorocebus aethiops; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D010450:Endopeptidases / Q000502:physiology; D019446:Endotoxemia / Q000276:immunology / Q000503:physiopathology; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006023:Glycoproteins / Q000502:physiology; D006505:Hepatitis / Q000276:immunology / Q000503:physiopathology*; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000503:physiopathology; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000503:physiopathology; D006525:Hepatitis, Viral, Human / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D019476:Insect Proteins / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000502:physiology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D007728:Kupffer Cells / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011425:Propionibacterium acnes / Q000276:immunology; D051381:Rats; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin / Q000502:physiology; D053724:Receptors, Interleukin-18; D015398:Signal Transduction; D051193:Toll-Like Receptors; D014162:Transfection; D019014:fas Receptor / Q000502:physiology
D029721:Drosophila Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D006023:Glycoproteins; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D019476:Insect Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; D019014:fas Receptor; C118370:interleukin-18 binding protein; D007371:Interferon-gamma; D010450:Endopeptidases; D020170:Caspase 1