Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor β1 and β2 chain expression

被引:181
作者
Braun, MC
He, JP
Wu, CY
Kelsall, BL
机构
[1] NIAID, Immune Cell Inteact Unit, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA
[2] NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA
关键词
interleukin; 12; monocytes; dendritic cells; Th1 and Th2 cells; cholera toxin;
D O I
10.1084/jem.189.3.541
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 alpha, but trot IL-10, IL-6, or transforming growth factor (TGF)-beta(1), by stimulated monocytes. The effects of CT were not due to autocrine production of IL-10, TGF-beta(1), or prostaglandin E-2. CT inhibited the production of IFN-gamma 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 beta 1 and beta 2 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 gamma. 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.
引用
收藏
页码:541 / 552
页数:12
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