The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/2/541/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 3, February 1, 1999 541-552

Articles

Cholera Toxin Suppresses Interleukin (IL)-12 Production and IL-12 Receptor β1 and β2 Chain Expression

Michael C. Braun*, Jianping He*, Chang-You Wu{ddagger}, and Brian L. Kelsall*

From the * Immune Cell Interaction Unit, Mucosal Immunity Section, and the {ddagger} Clinical Immunology Section, Laboratory for Clinical Investigation, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892

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)-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-{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 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 {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.

Key Words: interleukin 12 • monocytes • dendritic cells • Th1 and Th2 cells • cholera toxin

Address correspondence to Brian L. Kelsall, 10/11N238, 10 Center Dr., Bethesda, MD 20892-1890. Phone: 301-496-7473; Fax: 301-402-2240; E-mail: kelsall{at}nih.gov

Abbreviations used: CT, cholera toxin; DTH, delayed type hypersensitivity; LT, heat-labile toxin; SAC, Staphylococcus aureus, Cowan's strain I; sIgA, secretory immunoglobulin A.


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