Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice.
IL-18, produced as a biologically inactive precursor, is processed by caspase-1 in LPS-activated macrophages. Here, we investigated caspase-1-independent processing of IL-18 in Fas ligand (FasL)-stimulated macrophages and its involvement in liver injury. Administration of Propionibacterium acnes (P. acnes) upregulated functional Fas expression on macrophages in an IFNgamma-dependent manner, and these macrophages became competent to secrete mature IL-18 upon stimulation with FasL. This was also the case for caspase-1-deficient mice. Administration of recombinant soluble FasL (rFasL) after P. acnes priming induced comparable elevation of serum IL-18 in parallel with elevated serum liver enzyme levels. However, liver injury was not induced in IL-18-deficient mice after rFasL administration. These results indicate a caspase-1-independent pathway of IL-18 secretion from FasL-stimulated macrophages and its critical involvement in FasL-induced liver injury.
Tsutsui
H
H
Department of Immunology and Medical Zoology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
Kayagaki
N
N
Kuida
K
K
Nakano
H
H
Hayashi
N
N
Takeda
K
K
Matsui
K
K
Kashiwamura
S
S
Hada
T
T
Akira
S
S
Yagita
H
H
Okamura
H
H
Nakanishi
K
K
D000590:Amino Acid Chloromethyl Ketones; D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility; D019014:fas Receptor / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020382:Interleukin-18; D008562:Membrane Glycoproteins; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D020170:Caspase 1