Bone marrow-derived cells are major cellular components of human decidua, with macrophages comprising about 30% of the cells in term tissue. Because cytokines released by bone marrow-derived cells are known to affect hormone release in many tissues, we examined whether cytokines affect the release of PRL from human decidual cells. Exposure of primary decidual cell cultures from term pregnancies to tumor necrosis factor-alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, transforming growth factor-beta (TGF beta), and IL-8 caused dose-dependent inhibition of PRL release. Initial inhibition by each of the cytokines was noted after 24 h of exposure, and maximal inhibition of 33-60% occurred after 3 or 4 days. The maximal inhibitions by TNF alpha, IL-1 alpha, IL-1 beta, TGF beta, and IL-8 were 60%, 55%, 46%, 36%, and 33%, respectively, and the half-maximal effective doses of TNF alpha, IL-1 alpha, IL-1 beta, and TGF beta were 70, 2.8, 0.6, and 40 pM, respectively. The cytokine-induced decrease in decidual PRL release was accompanied by a decrease in PRL synthesis. In contrast to the other cytokines, IL-6 had no effect on basal PRL release. TNF alpha, IL-1 alpha, IL-1 beta, and IL-8 also inhibited stimulation of the synthesis and release of PRL and PRL mRNA levels in response to insulin. The effect of the cytokines was not due to inhibition of cell proliferation, because the DNA content of the cells was not affected by cytokine treatment. These results strongly suggest that cytokines released by decidual macrophages and other bone marrow-derived cells may have a paracrine role in the regulation of decidual PRL expression.