Prostaglandin E2 regulates both interleukin-2 and granulocyte- macrophage colony-stimulating factor gene expression in bovine lymphocytes

Prostaglandin E2 (PGE2) is known to inhibit interleukin-2 (IL-2) production by human peripheral blood lymphocytes (PBL) and to increase granulocyte-macrophage colony-stimulating factor (GM-CSF). In many species with hemochorial placentation, down-regulation of IL-2 appears necessary to impede early embryonic demise, whereas up-regulation of GM- CSF increases embryonic growth and survival. It is not known whether the same mechanisms are involved in a species with a less invasive placenta. PGE2 is synthesized during early bovine gestation by the endometrium and by the embryo, and it may therefore be involved in regulating IL-2 and GM-CSF in this species. Our goal was to evaluate the impact of PGE2 on cellular proliferation and on IL-2 and GM-CSF gene expression in bovine PBL. Incorporation of [3H]thymidine was used to study DNA synthesis. Gene expression was estimated by semiquantitative polymerase chain reaction using bovine-specific primers and by Northern analysis using amplified bovine cDNAs as probes. The DNA synthesis and IL-2 mRNA levels of bovine PBL stimulated by concanavalin A (ConA) were greatly reduced by PGE2 in direct- treatment studies. Under the same conditions, GM-CSF gene expression was also inhibited. However, pretreatment of PBL for 72 h with ConA and PGE2, followed, after washing, by an incubation with ConA alone for 12 h resulted in reduced DNA synthesis, stable expression of IL-2, and a dramatic increase of GM-CSF mRNA levels. This is the first evidence in the bovine model that direct treatment with PGE2 downregulates IL-2 and GM-CSF mRNA levels and that preconditioning with PGE2 stimulates GM- CSF gene expression. We propose that PGE2, either from embryonic or from endometrial compartments, induces bovine PBL to undergo functional changes, affecting cellular proliferation and cytokine production in order to accommodate the developing conceptus.