The effect of hydrocortisone on spontaneous human IgE and IgG4 production in atopic patients was studied. In cultures of mononuclear cells, hydrocortisone (HC) enhanced IgE and IgG4 production without affecting the production of IgM, IgA1, IgA2, IgG1, IgG2, or IgG3. In contrast, testosterone, beta-estradiol, progesterone, aldosterone, gonadotropin, and prolactin were without effect. HC had to be added at the initiation of culture to achieve this enhancing effect. IL-4 and IL-13 also enhanced spontaneous IgE and IgG4 production in mononuclear cells. However, the enhancement of IgE and IgG4 production by HC was not mediated by IL-4 or IL-13, as the addition of anti-IL-4 or anti-IL-13 Ab did not block the HC-induced enhancement. HC also enhanced IgE and IgG4 production in purified B cells, whereas neither IL-4 nor IL-13 did so. IL-5, IL-6, and TNF-alpha also enhanced IgE and IgG4 production in purified B cells; however, neither anti-IL-5, anti-IL-6, nor anti-TNF-alpha mAbs blocked the HC-induced enhancement. Purified surface (s)IgE+ and sIgG4+ B cells spontaneously produced IgE and IgG, respectively, whereas sIgE- and sIgG4- B cells failed to do so. HC enhanced IgE and IgG4 production in sIgE+ and sIgG4+ B cells, respectively, without affecting proliferation, whereas HC failed to induce IgE and IgG4 production in sIgE- and sIgG4- B cells, respectively. These results indicate that HC may selectively stimulate sIgE+ and sIgG4+ B cells.