Regulation of the factors governing IL-12R expression and IL-12 responsiveness has been shown to be important in the generation and stability of Th1- and Th2-type responses. In this regard, cytokines have been shown to have a prominent role in regulating IL-12R expression. In this study, the role that PGE2 and dexamethasone (DXM) have in regulating IL-12R expression was evaluated. Addition of PGE2 or DXM to human PBMCs stimulated with immobilized anti-CD3 plus IL-12 inhibited the production of IFN-gamma in a dose-responsive manner. Moreover, PBMCs stimulated with immobilized anti-CD3 in the presence of PGE2 or DXM for 3 days, washed extensively, and restimulated in the presence of IL-12 still did not produce IFN-gamma. This lack of IL-12 responsiveness from cells cultured in either PGE2 or DXM was correlated with diminished surface expression of IL-12Rbeta1, IL-12Rbeta2 mRNA expression, and IL-12 binding. Finally, the PGE2- and DXM-mediated inhibition of IL-12R expression was not affected significantly by addition of neutralizing Abs against either IL-4, IL-10, or TGF-beta. By contrast, addition of dibutyryl cAMP, 8-bromoadenosine 3:5 cAMP (8-Br-cAMP), or cholera toxin substantially reduced IL-12R expression, suggesting that PGE2 may be mediating its effects through enhancement of cAMP.