期刊
JOURNAL OF IMMUNOLOGY
卷 186, 期 9, 页码 5236-5243出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1001078
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资金
- National Institutes of Health [HL073965, HL083298, 5T32HL082547, AI53526, AI57153, AI56575, AI077949]
- Canadian Institutes for Health Research [MOP 44365]
- Leducq Foundation (European-North American Atrial Fibrillation Research Alliance) [07/CVD/03]
- James A. and Marion C. Grant Fund for Immunology Research
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-1 beta 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-1 beta 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: Ba2+-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 (LFE687C) combined with protective Ag protein had no effect on the currents. Furthermore, blocking Kir and Kv channels significantly decreased LeTx-induced release of IL-1 beta. In addition, retroviral transduction of macrophages with wild-type Kir enhanced LeTx-induced release of IL-1 beta, whereas transduction of dominant-negative Kir blocked LeTx-induced release of IL-1 beta. 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-1 beta involves an LF-protease effect that enhances Kir and Kv channel function during toxin stimulation. The Journal of Immunology, 2011, 186: 5236-5243.
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