ANTHRAX EDEMA TOXIN DIFFERENTIALLY REGULATES LIPOPOLYSACCHARIDE-INDUCED MONOCYTE PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 BY INCREASING INTRACELLULAR CYCLIC-AMP
ANTHRAX EDEMA TOXIN DIFFERENTIALLY REGULATES LIPOPOLYSACCHARIDE-INDUCED MONOCYTE PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 BY INCREASING INTRACELLULAR CYCLIC-AMP
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DOI：
10.1128/iai.62.10.4432-4439.1994
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发表时间：
1994-10-01
影响因子：
3.1
通讯作者：
CROSS, AS
中科院分区：
文献类型：
--
作者：
HOOVER, DL;FRIEDLANDER, AM;CROSS, AS
炭疽芽孢杆菌外毒素介导了严重炭疽病的大部分症状。除了可能由致死毒素刺激的巨噬细胞产生的细胞因子介导的感染性休克的临床症状外，感染患者还在感染部位表现出严重的水肿症。浮肿是由浮肿毒素(ET)介导的，它由结合分子、保护性抗原和具有内源性腺苷环化酶活性的活性部分--浮肿因子组成。细胞内环磷酸腺苷(CAMP)调节多种细胞因子的产生，调节水肿的形成，在宿主抵抗入侵细菌的防御中发挥重要作用。为了确定ET是否促进单核细胞内cAMP的积聚，从而影响细胞因子的产生，我们用内毒素(内毒素)和稀释的ET培养人单核细胞，并测定培养上清液中白介素6(IL-6)和肿瘤坏死因子α(TNF-α)的水平。我们通过逆转录聚合酶链式反应进一步估计了单核细胞中细胞因子特异性的mRNA积聚，并检测了ET处理后的细胞内cAMP浓度。内毒素和内毒素分别诱导单核细胞分泌等量的IL-6。ET不能抑制内毒素诱导的IL-6的产生，但在大多数实验中，ET对其有一定的促进作用。与这种对IL-6产生的刺激作用相反，ET诱导的肿瘤坏死因子-α的产生很少或根本没有。此外，ET还能显著抑制内毒素诱导的肿瘤坏死因子-α的合成。在ET处理的单核细胞中，这些调节现象也出现在与剂量相关的细胞内cAMP增加相关的mRNA水平上。用cAMP的活性类似物二丁酰cAMP处理的单核细胞，产生的细胞因子模式与用ET处理的细胞相同。由于ET诱导的人单核细胞内cAMP不受调控地积聚，导致细胞因子网络的破坏，可能会削弱细胞的抗菌反应，并导致临床症状和体征。
Bacillus anthracis exotoxins mediate most of the symptomatology of severe anthra?r. In addition to a clinical syndrome reminiscent of septic shock, which may be mediated by cytokines produced by macrophages stimulated with lethal toxin, infected patients show profound edema at sites of infection. Edema is mediated by edema toxin (ET), which comprises of a binding molecule, protective antigen, and an active moiety, edema factor, which possesses intrinsic adenylyl cyclase activity. Intracellular cyclic AMP (cAMP) regulates the production of several cytokines that modulate edema formation and play important roles in host defense against invading bacteria. To determine whether ET enhanced the accumulation of cAMP in monocytes and thereby influenced cytokine production, we cultured human monocytes with endotoxin (lipopolysaccharide [LPS]) and dilutions of ET and determined the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in culture supernatant fluids. We further estimated cytokine-specific mRNA accumulation in monocytes by reverse transcription PCR and examined intracellular cAMP concentrations following treatment with ET. ET and LPS each induced monocytes to secrete comparable amounts of IL-6. ET did not inhibit and in most experiments modestly enhanced LPS-induced IL-6 production. In contrast to this stimulatory effect on IL-6 production, ET induced little or no TNF-alpha production. Moreover, ET profoundly inhibited LPS-induced TNF-alpha synthesis. These regulatory phenomena were also observed at the mRNA level in association with dose-related enhancement of intracellular cAMP in ET-treated monocytes. Monocytes treated with dibutyryl cAMP, an active analog of cAMP, produced cytokines in a pattern identical to that of cells treated with ET. ?he disruption of cytokine networks as a consequence of unregulated, ET-induced cAMP accumulation in human monocytes may impair cellular antimicrobial responses and contribute to clinical signs and symptoms.