Cholera toxin and heat-labile enterotoxin activate human monocyte-derived dendritic cells and dominantly inhibit ctokine production through a cyclic AMP-dependent pathway
Cholera toxin and heat-labile enterotoxin activate human monocyte-derived dendritic cells and dominantly inhibit ctokine production through a cyclic AMP-dependent pathway
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DOI：
10.1128/iai.70.10.5533-5539.2002
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发表时间：
2002-10-01
影响因子：
3.1
通讯作者：
Lewis, GK
中科院分区：
文献类型：
--
作者：
Bagley, KC;Abdelwahab, SF;Lewis, GK
霍乱毒素（CT）和不耐热肠毒素（LT）是强有力的粘膜佐剂，其细胞靶点和作用机制尚不清楚。有新的证据表明，树突状细胞（DC）是介导这些毒素在体内的佐剂作用的主要细胞类型之一。在这里，我们研究了CT和LT对体外培养的人单核细胞来源的DC（MDDC）成熟的影响。我们发现，一个酶活性的A域是必要的CT和LT诱导MDDC的成熟，这种激活是严格的环AMP（CAMP）依赖。ADP-核糖基化缺陷的衍生物，这些毒素未能诱导MDDC的成熟，而二丁酰环-3 '，5'-AMP和毛喉素模拟CT和LT诱导的MDDC的成熟。此外，cAMP依赖性激酶的抑制剂，RP-8-Br-cAMP，阻断CT，LT和毛喉素激活MDDC的能力。CT、LT、二丁酰-环-3 '，5'-AMP和Forskolin在饱和浓度脂多糖存在下也显著抑制MDDC产生白细胞介素12和肿瘤坏死因子α。综上所述，这些结果表明CT和LT对MDDC的作用是由cAMP介导的。
Cholera toxin (CT) and heat-labile enterotoxin (LT) are powerful mucosal adjuvants whose cellular targets and mechanism of action are unknown. There is emerging evidence that dendritic cells (DC) are one of the principal cell types that mediate the adjuvant effects of these toxins in vivo. Here we investigate the effects of CT and LT on the maturation of human monocyte-derived DC (MDDC) in vitro. We found that an enzymatically active A domain is necessary for both CT and LT to induce the maturation of MDDC and that this activation is strictly cyclic AMP (CAMP) dependent. ADP-ribosylation-defective derivatives of these toxins failed to induce maturation of MDDC, whereas dibutyryl-cyclic-3',5'-AMP and Forskolin mimic the maturation of MDDC induced by CT and LT. In addition, an inhibitor of cAMP-dependent kinases, Rp-8-Br-cAMPs, blocked the ability of CT, LT, and Forskolin to activate MDDC. CT, LT, dibutyryl-cyclic-3',5'-AMP, and Forskolin also dominantly inhibit interleukin 12 and tumor necrosis factor alpha production by MDDC in the presence of saturating concentrations of lipopolysaccharide. Taken together, these results show that the effects of CT and LT on MDDC are mediated by cAMP.