Anthrax lethal factor activates K(+) channels to induce IL-1β secretion in macrophages.
نویسندگان
چکیده
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.
منابع مشابه
The Anti-Tumorigenic Mushroom Agaricus blazei Murill Enhances IL-1β Production and Activates the NLRP3 Inflammasome in Human Macrophages
Agaricus blazei Murill (AbM) has been reported to possess immune activity against tumors and infections through stimulation of mononuclear phagocytes. Recently, AbM extract was shown to induce the production of the pro-inflammatory cytokine, interleukin-1β (IL-1β), in human monocytes. IL-1β is a key pro-inflammatory cytokine produced by activated macrophages and monocytes and its secretion is s...
متن کاملType I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells
Influenza A virus (IAV) triggers a contagious and potentially lethal respiratory disease. A protective IL-1β response is mediated by innate receptors in macrophages and lung epithelial cells. NLRP3 is crucial in macrophages; however, which sensors elicit IL-1β secretion in lung epithelial cells remains undetermined. Here, we describe for the first time the relative roles of the host innate rece...
متن کاملFIVE ALPHA DIHYDROTESTOSTERONE (5α-DHT) MAY MODULATE NITRIC OXIDE RELEASE VIA ENDOGENOU S CYTOKINES IN PERITONEAL MA CROPHA GES OF NZB/BALBc MICE
Recent studies have established that sex hormones directly or indirectly affect T and B cells and macrophages by manipulating the production of cytokines. In this study the possibility of the effect of 5a-DHT on macrophage (MΦ) nitric oxide (NO) release via interleukin-l, 6 (lL-1β, IL-6) or tumor necrosis factor-a (TNFα) was investigated. The endogenous cytokines IL-1β, IL-6 and TNF-α were ...
متن کاملResident CD11c+ lung cells are impaired by anthrax toxins after spore infection.
Bacillus anthracis secretes 2 toxins: lethal toxin (LT) and edema toxin (ET). We investigated their role in the physiopathologic mechanisms of inhalational anthrax by evaluating murine lung dendritic cell (LDC) functions after infection with B. anthracis strains secreting LT, ET, or both or with a nontoxinogenic strain. Three lung cell populations gated on CD11c/CD11b expression were obtained a...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Journal of immunology
دوره 186 9 شماره
صفحات -
تاریخ انتشار 2011