title: Anthrax lethal factor activates K(+) channels to induce IL-1β secretion in macrophages.
abstract: Anthrax lethal toxin (LeTx) is a virulence factor of Bacilillus anthracis that is a bivalent toxin, containing lethal factor (LF) and protective Ag proteins, which causes cytotoxicity and altered macrophage function. LeTx exposure results in early K(+) efflux from macrophages associated with caspase-1 activation and increased IL-1β release. The mechanism of this toxin-induced K(+) efflux is unknown. The goals of the current study were to determine whether LeTx-induced K(+) efflux from macrophages is mediated by toxin effects on specific K(+) channels and whether altered K(+)-channel activity is involved in LeTx-induced IL-1β release. Exposure of macrophages to LeTx induced a significant increase in the activities of two types of K(+) channels that have been identified in mouse macrophages: Ba(2+)-sensitive inwardly rectifying K(+) (Kir) channels and 4-aminopyridine-sensitive outwardly rectifying voltage-gated K(+) (Kv) channels. LeTx enhancement of both Kir and Kv required the proteolytic activity of LF, because exposure of macrophages to a mutant LF-protein (LF(E687C)) combined with protective Ag protein had no effect on the currents. Furthermore, blocking Kir and Kv channels significantly decreased LeTx-induced release of IL-1β. In addition, retroviral transduction of macrophages with wild-type Kir enhanced LeTx-induced release of IL-1β, whereas transduction of dominant-negative Kir blocked LeTx-induced release of IL-1β. Activation of caspase-1 was not required for LeTx-induced activation of either of the K(+) channels. These data indicate that a major mechanism through which LeTx stimulates macrophages to release IL-1β involves an LF-protease effect that enhances Kir and Kv channel function during toxin stimulation.
authors.affiliation: Section of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Johnson
authors.initials: J
authors.lastname: Thomas
authors.forename: Yulia
authors.initials: Y
authors.lastname: Epshtein
authors.forename: Arun
authors.initials: A
authors.lastname: Chopra
authors.forename: Balazs
authors.initials: B
authors.lastname: Ordog
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ghassemi
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: James L
authors.initials: JL
authors.lastname: Cook
authors.forename: Irena
authors.initials: I
authors.lastname: Levitan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000276:immunology / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D053583:Interleukin-1beta; D015221:Potassium Channels; C030325:anthrax toxin