BROMOCRIPTINE HAS LITTLE DIRECT EFFECT ON MURINE LYMPHOCYTES, THE IMMUNOMODULATORY EFFECT BEING MEDIATED BY THE SUPPRESSION OF PROLACTIN SECRETION

We investigated whether the immunosuppressive effect of bromocriptine in mice is due to its direct effect on lymphocyte functions or through inhibition of prolactin secretion. Incubation of mouse Babl/c splenic lymphocytes. with bromocriptine in vitro at a concentration of around 0.5 to 1 mu g/mL causes an inhibition of antigen- or mitogen-induced proliferation. However, bromocriptine in vitro has no effect on lympho kine production (gamma-interferon and interleukin-2), expression of in terleukin-2 receptor or lymphocyte cytotoxic function. Furthermore, tr eatment of Babl/c mice with bromocriptine inhibits the mixed lymphocyt e reaction and mitogen stimulation, as well as primary and secondary a ntibody production. However, eve postulated that the inhibition of ex vivo functional activity could not account for a direct cytostatic or cytotoxic effect of bromocriptine. This is supported by the in vitro d ata, which shows that bromocriptine has no effect on proliferating P-8 15 mastocytoma tumor cells. Finally, (NZB/NZW) Fl mice spontaneously d evelop a disease similar to systemic lupus erythematosus. In both non- autoimmune Babl/c mice and (NZB/NZW) Fl lupus-mice, the serum level of bromocriptine achieved by a treatment with 5 mg/kg on average is 2-6 ng/mL. On tile one hand, this dose is sufficient to significantly alte r the ex vivo functional tests in Babl/c mice and to show a beneficial effect in the in vivo model of female lupus-mice. On the other hand, the lowest concentration which could have an inhibitory effect an anti gen- and mitogen-induced proliferation in vitro is 200 ng/mL, ie 50 ti mes more than that required in vivo to obtain significant reductions o f proteinurea, glomerular membrane proliferation and immune deposits i n lupus-mice. Thr serum levels of gamma-interferon and interleukin-2, are reduced in lupus-mice when compared with Babl/c mice. The treatmen t with bromocriptine does not influence these parameters. In conclusio n, our data demonstrate that the major immunosuppressive activity of b romocriptine is probably dependent on its hypoprolactinemic effect.