title: Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta.
abstract: IL-18, produced as biologically inactive precursor, is secreted from LPS-stimulated macrophages after cleavage by caspase-1. In this study, we investigated the mechanism underlying caspase-1-mediated IL-18 secretion. Kupffer cells constantly stored IL-18 and constitutively expressed caspase-1. Inhibition of new protein synthesis only slightly reduced IL-18 secretion, while it decreased and abrogated their IL-1beta and IL-12 secretion, respectively. Kupffer cells deficient in Toll-like receptor (TLR) 4, an LPS-signaling receptor, did not secrete IL-18, IL-1beta, and IL-12 upon LPS stimulation. In contrast, Kupffer cells lacking myeloid differentiation factor 88 (MyD88), an adaptor molecule for TLR-mediated-signaling, secreted IL-18 without IL-1beta and IL-12 production in a caspase-1-dependent and de novo synthesis-independent manner. These results indicate that MyD88 is essential for IL-12 and IL-1beta production from Kupffer cells while their IL-18 secretion is mediated via activation of endogenous caspase-1 without de novo protein synthesis in a MyD88-independent fashion after stimulation with LPS. In addition, infection with Listeria monocytogenes, products of which have the capacity to activate TLR, increased serum levels of IL-18 in wild-type and MyD88-deficient mice but not in caspase-1-deficient mice, whereas it induced elevation of serum levels of IL-12 in both wild-type and caspase-1-deficient mice but not in MyD88-deficient mice. Taken together, these results suggested caspase-1-dependent, MyD88-independent IL-18 release in bacterial infection.
authors.affiliation: First Department of Surgery, Department of Immunology & Medical Zoology, Department of Otolaryngology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Seki
authors.forename: H
authors.initials: H
authors.lastname: Tsutsui
authors.forename: H
authors.initials: H
authors.lastname: Nakano
authors.forename: N
authors.initials: N
authors.lastname: Tsuji
authors.forename: K
authors.initials: K
authors.lastname: Hoshino
authors.forename: O
authors.initials: O
authors.lastname: Adachi
authors.forename: K
authors.initials: K
authors.lastname: Adachi
authors.forename: S
authors.initials: S
authors.lastname: Futatsugi
authors.forename: K
authors.initials: K
authors.lastname: Kuida
authors.forename: O
authors.initials: O
authors.lastname: Takeuchi
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: J
authors.initials: J
authors.lastname: Fujimoto
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D029721:Drosophila Proteins; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008089:Listeria monocytogenes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D004792:Enzyme Precursors; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011498:Protein Precursors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12; D020169:Caspases; D020170:Caspase 1