The effects of human prolactin on enriched peripheral B lymphocytes obtained from healthy males were examined. Immunoregulation by prolactin was studied in B cells activated with either anti-IgM alone, or anti-IgM antibodies and recombinant interleukin-2 (r-IL-2), as well as control resting B cells. Expression of IL-2 receptors (IL-2R), and IgM and IgG in the culture supernatants were used as a measure of B cell activation and differentiation. Prolactin significantly synergized with IL-2 in the enhancement of surface expression of IL-2R on anti-IgM treated B cells. Although no differentiating effect was observed on resting B cells, prolactin (0.2-100 ng/ml) exhibited a dose-dependent enhancement upon both IgM and IgG secretion from B cells treated with anti-IgM and IL-2. In the absence of exogenously added IL-2 similar differentiating effect were observed in B cells treated with anti-IgM at prolactin concentrations of 0.2-10 ng/ml, but not 100 ng/ml. Thus, the present results demonstrate the modulatory effect of prolactin on activation and differentiation of anti-IgM triggered human B cells, and emphasize the importance of co-stimulatory signal mediated by IL-2 in B cell responses to high prolactin levels. These findings extend the immunoregulatory effects of prolactin, previously confirmed for T cells, to the B cell arm of the immune response, and suggest an important role of prolactin in mediating adaptation and communication between the nerve and immune systems.