Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor beta1 and beta2 chain expression

J Exp Med. 1999 Feb 1;189(3):541-52. doi: 10.1084/jem.189.3.541.


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 not IL-10, IL-6, or transforming growth factor (TGF)-beta1, by stimulated monocytes. The effects of CT were not due to autocrine production of IL-10, TGF-beta1, or prostaglandin E2. 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 beta1 and beta2 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.

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • CD3 Complex / immunology
  • Cholera Toxin / immunology*
  • Cholera Toxin / pharmacology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / biosynthesis*
  • Interleukin-12 / genetics
  • Lipopolysaccharides / immunology
  • Mice
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Mucous Membrane / immunology
  • RNA, Messenger / isolation & purification
  • Receptors, Interleukin / biosynthesis*
  • Receptors, Interleukin-12
  • Th1 Cells / immunology
  • Th2 Cells / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Adjuvants, Immunologic
  • CD3 Complex
  • IL12RB1 protein, human
  • IL12RB2 protein, human
  • Il12rb1 protein, mouse
  • Il12rb2 protein, mouse
  • Lipopolysaccharides
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma
  • Cholera Toxin