Atopic dermatitis (AD) is a chronic skin disorder associated with elevated serum IgE and colonization of the skin by Staphylococi which secrete toxins with superantigenic activity. The present study examined the immunomodulatory effects of toxic shock syndrome toxin (TSST)-1, a prototypic superantigen, on IgE synthesis by interleukin (IL)-4-stimulated peripheral blood mononuclear cells (PBMC) from five patients with AD and five normal subjects. TSST-1 inhibited IL-4-induced IgE synthesis by AD and normal PBMC (P < 0.05). In contrast, IgG synthesis was not similarly affected (P > 0.30). Inhibition of IL-4-induced IgE production was associated with induction of interferon (IFN)-gamma synthesis by TSST-1 (P < 0.02). Normal PBMC synthesized significantly more (P < 0.005) IFN-gamma than AD PBMC. A neutralizing antibody to IFN-gamma reversed TSST-1-induced suppression of IgE synthesis by the normal PBMC (P < 0.03), but not the AD PBMC. In AD, but not normal, PBMC anti-IFN-alpha antibody reversed the suppression of IgE synthesis induced by TSST-1. These results demonstrate that TSST-1 uses different mechanisms for modulation of IgE synthesis in AD versus normal PBMC. Furthermore, the reversal of TSST-1-induced suppression of IgE synthesis in AD PBMC by anti-IFN-alpha, but not anti-IFN-gamma, is consistent with the concept that AD is associated with defective Th1 cell function and enhanced monocyte activity.