Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines

Glucocorticoids, at concentrations mimicking stress-physiologic plasma leve ls, 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 respo nse. The mechanisms of these immune alterations are currently unknown but m ay involve modulation of key cytokines known to regulate the type 1/type 2 cytokine balance. Therefore, we sought to determine the role of cytokines p reviously reported to regulate the type 1/type 2 cytokine balance, includin g 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 toroid in the presence o f 10(-8) M dexamethasone (DEX). Cultures were supplemented with recombinant human (rHuIL-12), rHuLFN-gamma, or neutralizing monoclonal antibodies (mAb ) against IL-4, IL-10, or IL-13. DEX decreased IFN-gamma production and inc reased IL-4 and IL-10 production by tetanus-stimulated PBMC. The addition o f either recombinant IL-12p70 or IFN-gamma abrogated the DEX-mediated decre ase in IFN-gamma and increase in IL-4 production. Neutralization of IL-4 ac tivity partially abrogated the DEX-induced alterations in IFN-gamma and IL- 4, but not IL-1o, production. Neutralization of IL-10 or IL-13 had no effec t on the Dex-mediated type 1/type 2 cytokine alterations. Therefore, the DE X-mediated type 1/type 2 cytokine alterations in tetanus-stimulated PBMC ar e primarily the result of downregulation of type 1 cytokines, subsequently permitting the production of type 2 cytokines.