Oxygen regulation of macrophage migration inhibitory factor in human placenta

Abstract

dio S, Paulesu L, Caniggia I. Oxygen regulation of macrophage migration inhibitory factor in human placenta. Am J Physiol Endocrinol Metab 292: E272-E280, 2007. First published August 29, 2006; doi:10.1152/ajpendo.00086.2006.-Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine involved in regulation of macrophage function. In addition, MIF may also play a role in murine and human reproduction. Although both first trimester trophoblast and decidua express MIF, the regulation and functional significance of this cytokine during human placental development remains unclear. We assessed MIF expression throughout normal human placental development, as well as in in vitro (chorionic villous explants) and in vivo (high altitude placentae) models of human placental hypoxia. Dimethyloxalylglycine (DMOG), which stabilizes hypoxia inducible factor-1 under normoxic conditions, was also used to mimic the effects of hypoxia on MIF expression. Quantitative real-time PCR and Western blot analysis showed high MIF protein and mRNA expression at 7-10 wk and lower levels at 11-12 wk until term. Exposure of villous explants to 3% O2 resulted in increased MIF expression and secretion relative to standard conditions (20% O2). DMOG treatment under 20% O2 increased MIF expression. In situ hybridization and immunohistochemistry showed elevated MIF expression in low oxygen-induced extravillous trophoblast cells. Finally, a significant increase in MIF transcript was observed in placental tissues from high-altitude pregnancies. Hence, three experimental models of placental hypoxia (early gestation, DMOG treatment, and high altitude) converge in stimulating increased MIF, supporting the conclusion that placental-derived MIF is an oxygen-responsive cytokine highly expressed in physiological in vivo and in in vitro low oxygen conditions. hypoxia; human trophoblast; proinflammatory cytokines.IMPORTANT ASPECTS of placental development are regulated by changes in O 2 tension. During the early stages of pregnancy (prior to 10 -12 wk of gestation), the trophoblast is in a low-oxygen environment due to the absence of maternal blood flow in the intervillous space (36). With advancing gestation, the maternal circulation becomes fully established and PO 2 increases (22). Both in vivo and in vitro studies support that the low-oxygen environment is required for embryo development and the balance of trophoblast proliferation/differentiation essential for early placental development. Likewise, the late firstand second-trimester increase in PO 2 is critical to complete the process of trophoblast differentiation/invasion (3, 18).An increasing body of evidence indicates that oxygen tension modifies the expression and activity of a variety of regulatory genes that govern trophoblast differentiation. We (28) have recently shown that oxygen is involved in the modulation of focal adhesion kinase, a key signaling molecule regulating trophoblast proliferation and invasion. In addition, we (16) have reported that the early events of ...

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