Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines.
Glucocorticoids, at concentrations mimicking stress-physiologic plasma levels, cause an in vitro shift in the type 1/type 2 cytokine balance of human peripheral blood mononuclear cells (PBMC) toward a predominant type 2 response. The mechanisms of these immune alterations are currently unknown but may involve modulation of key cytokines known to regulate the type 1/type 2 cytokine balance. Therefore, we sought to determine the role of cytokines previously reported to regulate the type 1/type 2 cytokine balance, including interleukin-12 (IL-12), interferon-gamma (IFN-gamma, IL-10, IL-4, and IL-13, in the glucocorticoid-mediated human type 1/type 2 cytokine alterations. Human PBMC were stimulated in vitro with tetanus toxoid in the presence of 10(-8) M dexamethasone (DEX). Cultures were supplemented with recombinant human (rHuIL-12), rHuIFN-gamma, or neutralizing monoclonal antibodies (mAb) against IL-4, IL-10, or IL-13. DEX decreased IFN-gamma production and increased IL-4 and IL-10 production by tetanus-stimulated PBMC. The addition of either recombinant IL-12p70 or IFN-gamma abrogated the DEX-mediated decrease in IFN-gamma and increase in IL-4 production. Neutralization of IL-4 activity partially abrogated the DEX-induced alterations in IFN-gamma and IL-4, but not IL-10, production. Neutralization of IL-10 or IL-13 had no effect on the Dex-mediated type 1/type 2 cytokine alterations. Therefore, the DEX-mediated type 1/type 2 cytokine alterations in tetanus-stimulated PBMC are primarily the result of downregulation of type 1 cytokines, subsequently permitting the production of type 2 cytokines.
Agarwal
S K
SK
Division of Allergy and Clinical Immunology, The University of Texas Houston Medical School, Houston, TX 77030, USA.
Marshall
G D
GD
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D013312:Stress, Physiological / Q000276:immunology / Q000378:metabolism; D013744:Tetanus Toxin / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018793:Interleukin-13; D013744:Tetanus Toxin; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D003907:Dexamethasone; D007371:Interferon-gamma