Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor beta1 and beta2 chain expression.
Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor beta1 and beta2 chain expression.
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DOI：
10.1084/jem.189.3.541
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发表时间：
1999-02-01
影响因子：
15.3
通讯作者：
Kelsall, B L
中科院分区：
文献类型：
--
作者：
Braun, M C;He, J;Wu, C Y;Kelsall, B L
霍乱毒素（CT）是一种强有力的粘膜疫苗佐剂，它已被证明可诱导全身和粘膜组织中的辅助性T细胞2型（Th 2）应答。我们报告CT抑制白细胞介素（IL）-12（一种主要的Th 2反调节细胞因子）的产生。CT以剂量依赖性方式抑制刺激的人单核细胞产生IL-12 p70。这种抑制发生在基因转录水平，在低浓度的CT时最大，并且依赖于毒素的A亚基，因为纯化的CT B亚基具有最小的作用。CT还抑制单核细胞来源的树突状细胞产生IL-12 p70，以及刺激的单核细胞产生肿瘤坏死因子α，但不抑制IL-10、IL-6或转化生长因子（TGF）-β1。CT的作用不是由于IL-10、TGF-β1或前列腺素E2的自分泌产生。CT抑制抗CD 3刺激的人外周血单个核细胞产生IFN-γ，部分原因是抑制IL-12的产生，但也抑制T细胞上IL-12受体β1和β2链的表达。在体内，在用脂多糖进行全身性攻击之前给予CT的小鼠的血清IL-12 p40和干扰素γ水平显著降低。这些数据证明了CT可以抑制Th 1免疫应答的两种新机制，并有助于解释粘膜给药CT增强Th 2依赖性免疫应答的能力。
Cholera toxin (CT) is a potent mucosal vaccine adjuvant, which has been shown to induce T helper cell type 2 (Th2) responses in systemic and mucosal tissues. We report that CT inhibits the production of interleukin (IL)-12, a major Th2 counterregulatory cytokine. IL-12 p70 production by stimulated human monocytes was inhibited by CT in a dose-dependent manner. This suppression occurred at the level of gene transcription, was maximal at low concentrations of CT, and was dependent on the A subunit of the toxin, since purified CT B subunit had minimal effect. CT also inhibited the production of IL-12 p70 by monocyte-derived dendritic cells, as well as the production of tumor necrosis factor α, but not IL-10, IL-6, or transforming growth factor (TGF)-β1, by stimulated monocytes. The effects of CT were not due to autocrine production of IL-10, TGF-β1, or prostaglandin E2. CT inhibited the production of IFN-γ by anti-CD3-stimulated human peripheral blood mononuclear cell, due in part to suppression of IL-12 production, but also to the inhibition of expression of the β1 and β2 chains of the IL-12 receptor on T cells. In vivo, mice given CT before systemic challenge with lipopolysaccharide had markedly reduced serum levels of IL-12 p40 and interferon γ. These data demonstrate two novel mechanisms by which CT can inhibit Th1 immune responses, and help explain the ability of mucosally administered CT to enhance Th2-dependent immune responses.