IL-4 specifically induces IgE antibody production by mononuclear cells (MNC) from healthy nonatopic donors. At least part of the effect of IL-4 is indirect since IgE-induced synthesis also requires CD4+ T cells and, to a lesser extent, monocytes. The IL-4-mediated IgE synthesis is enhanced by IL-2, IL-5 and IL-6 and suppressed by IFN-γ, IFN-α and PGE2. In vitro IFN-γ plays a central role in the down-regulation of IL-4-induced IgE synthesis. Interestingly, studies performed with atopic donors indicated that IL-4 and IFN-γ may also be operational in vivo. Moreover, IL-4 inhibits the IFN-γ synthesis, which indicates that these two cytokines regulate IgE synthesis by inhibiting each other’s activities and synthesis. In addition, it was demonstrated that IgE production is associated with the expression of the FcεRII/CD23 antigen and its soluble part (sCD23). However, the expression of CD23 and the release of sCD23 does not strictly correlate with the production of IgE since also highly purified B cells express CD23 to the same extent as MNC but without producing IgE. Production of IgE can only be achieved by addition of CD4+ T cells, suggesting that sCD23 also acts indirectly on B cells and may have a possible activity on T cells. The addition of sCD23 to MNC does not induce IgE production in the absence of IL-4. These data indicate that the release of sCD23 in itself, even in the presence of T cells, is not sufficient for triggering the B cells to produce IgE antibodies. In conclusion, our findings demonstrate that IL-4-induced IgE production in human involves complex interactions between B cells and at least T cells and monocytes and is positively modulated by IL-2, IL-5, IL-6 and sCD23 and down-regulated by IFN-γ, IFN-α, and PGE2.