title: Anthrax lethal toxin rapidly activates caspase-1/ICE and induces extracellular release of interleukin (IL)-1beta and IL-18.
abstract: Anthrax lethal toxin (LT), a critical virulence factor for Bacillus anthracis, has been demonstrated to cleave and to inactivate mitogen-activated protein kinase kinases (MAPKKs) that propagate prosurvival signals in macrophages (1-5). Whether this action of anthrax LT leads to the production of proinflammatory cytokines by macrophages has been more controversial (6, 7). We now report that anthrax LT treatment leads to the specific extracellular release of interleukin (IL)-1beta and IL-18 by the murine macrophage cell lines, RAW264.7 and J774A.1. Studies of the processing of IL-1beta reveal that the levels of activated/cleaved IL-1beta in RAW264.7 and J774.A1 cells are increased following treatment with anthrax LT. Enhanced processing of IL-1beta directly correlates with increased levels in the activation of its upstream regulator, IL-1beta-converting enzyme/Caspase-1 (ICE). The extracellular release of IL-1beta and IL-18 in response to anthrax LT is ICE-dependent, as an ICE-specific inhibitor blocks this process. These data indicate that ICE, IL-1beta, and IL-18 are downstream effectors of anthrax LT in macrophages, providing the basis for new bioassays for anthrax LT activity and representing potential therapeutic targets.
authors.affiliation: Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. frucht@cber.fda.gov
authors.forename: Ruth
authors.initials: R
authors.lastname: Cordoba-Rodriguez
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.forename: Carla S R
authors.initials: CS
authors.lastname: Lankford
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000494:pharmacology*; D020170:Caspase 1 / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005110:Extracellular Space / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; D011994:Recombinant Proteins; C030325:anthrax toxin; D020170:Caspase 1