TGF-β2 and PGE2 in Rabbit Blastocoelic Fluid Can Modulate GM-CSF Production by Human Lymphocytes

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Abstract
During normal pregnancy, major changes occur in the production of Th2/Th1 cytokines at the feto-maternal interface. Th2 cytokines such as interleukin-4 (IL-4) or interleukin-10 (IL-10) are predominantly produced locally in the uterine and placental tissues, whereas the production of Th1 cytokines such as tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) are decreased. Because these modulation might be induced by the embryo, the current study was carried out to test the effect of rabbit blastocoelic fluid on the production of Th2/Th1 cytokines by lymphocytes, and to investigate the possible implication of transforming growth factor beta 2 (TGF-beta 2) prostaglandin E2 (PGE2) as modulators of the production of these cytokines. Human peripheral blood lymphocytes (PBL) were cultured along with ConcanavalinA(Con A), and rabbit blastocoelic fluid was collected on day 12 of gestation (BF d-12). Concentrations of cytokines in culture media were determined by enzyme-linked immunoadsorbent assay (ELISA). Addition of BF d-12 in the culture medium induced a strong inhibition of IL-2, TNF-alpha, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) production. However, an initial pretreatment of the lymphocytes with BF d-12, followed by a Con A stimulation, led to a marked increase in GM-CSF production, whereas IL-2, TNF-alpha, and IL-10 secretions were inhibited. It was also demonstrated, for the first time, that a pretreatment of the lymphocytes with TGF-beta 2 and PGE2 increased GM-CSF production to the same level reached after the addition of BF d-12. Furthermore, removal of TGF-beta 2 and PGE2 from BF d-12 by affinity chromatography reduced the effect of BF d-12 on GM-CSF production. Taken together, these findings suggest that the embryo, in modulating harmful and beneficial cytokine production locally, plays an active role in its protection against maternal immune cellular assault. These results also emphasize the importance of growth factors for successfully maintaining pregnancy.

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