Immunoendocrine mechanisms in mammary tumor progression: direct prolactin modulation of peripheral and preneoplastic hyperplastic-alveolar-nodule- infiltrating lymphocytes

Abstract

We have previously shown that the immunoregulatory function of prolactin may play a role in the progression of the mouse mammary preneoplastic hyperplastic alveolar nodule (HAN) line C4 to carcinoma. In this study we investigated the direct effect of prolactin on lymphocytes isolated from normal and C4-HAN-bearing mice. In addition, we tested the effect of ovariectomy on prolactin/lymphocyte interaction to see whether, as has been reported in rats [Mukherjee P., Hymer W. C. (1992) Prog Neuroendocrinol Immunol 5: 108; Viselli S. M. et al. (1991) Endocrinology 129: 983], removal of estrogen would enhance the response to prolactin in mice. Proliferation of splenocytes, lymph node cells and HAN-infiltrating lymphocytes was stimulated by prolactin in a dose-responsive fashion. Ovariectomy did not alter this effect consistently. Cell-cycle analysis based on simultaneous staining of DNA and RNA revealed that prolactin-stimulated lymphocytes progress through all phases of the cell cycle whereas anti-prolactin antiserum inhibits this stimulation. Two-color flow-cytometric analysis revealed the time-dependent induction of interleukin-2 (IL-2) receptor expression on both CD4+ and CD8+ cells by prolactin. Prolactin-treated lymphocytes also produced low yet detectable levels of bioactive IL-2 in a dose- and time-dependent fashion. Prolactin enhanced lymphocyte responsiveness to mitogens and showed a marked synergism at suboptimal concentrations. Pretreatment of splenocytes from HAN bearers with a high concentration of prolactin slightly enhanced natural killer (NK) activity; anti-prolactin antiserum reduced the NK lytic activity of poly(I).poly(C)-activated splenocytes from HAN-bearing mice. Our results provide direct experimental evidence for the stimulatory effect of prolactin on lymphocyte function and IL-2-mediated lymphocyte proliferation and suggest a mechanism linking the endocrine system to immunomediated enhancement of HAN progression.