title: Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin.
abstract: The potassium ionophore nigericin induces cell death and promotes the maturation and release of IL-1beta in lipopolysaccharide (LPS)-primed monocytes and macrophages, the latter depending on caspase-1 activation by an unknown mechanism. Here, we investigate the pathway that triggers cell death and activates caspase-1. We show that without LPS priming, nigericin alone triggered caspase-1 activation and IL-18 generation in THP-1 monocytic cells. Simultaneously, nigericin induced caspase-1-independent necrotic cell death, which was blocked by the cathepsin B inhibitor CA-074-Me and other cathepsin inhibitors. Cathepsin B activation after nigericin treatment was determined biochemically and corroborated by rapid lysosomal leakage and translocation of cathepsin B to the cytoplasm. IL-18 maturation was prevented by both caspase-1 and cathepsin B inhibitors in THP-1 cells, primary mouse macrophages and human blood monocytes. Moreover, IL-18 generation was reduced in THP-1 cells stably transformed either with cystatin A (an endogenous cathepsin inhibitor) or antisense cathepsin B cDNA. Collectively, our study establishes a critical role for cathepsin B in nigericin-induced caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Republic of Singapore.
authors.forename: H
authors.initials: H
authors.lastname: Hentze
authors.forename: X Y
authors.initials: XY
authors.lastname: Lin
authors.forename: M S K
authors.initials: MS
authors.lastname: Choi
authors.forename: A G
authors.initials: AG
authors.lastname: Porter
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002154:Calpain / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D009336:Necrosis; D009550:Nigericin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects
chemical_list: D001427:Bacterial Toxins; C400541:CA 074 methyl ester; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D020382:Interleukin-18; D008070:Lipopolysaccharides; D002154:Calpain; D002401:Cathepsin B; D020170:Caspase 1; D009550:Nigericin