title: Oxygen regulation of macrophage migration inhibitory factor in human placenta.
abstract: 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% O(2) resulted in increased MIF expression and secretion relative to standard conditions (20% O(2)). DMOG treatment under 20% O(2) 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.
authors.affiliation: Dept. of Physiology, Division of Immunoendocrinology and Reproductive Physiology, Univ. of Siena, 53100 Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ietta
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Roberta
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Nima
authors.initials: N
authors.lastname: Soleymanlou
authors.forename: Barbara
authors.initials: B
authors.lastname: Orsini
authors.forename: Stacy
authors.initials: S
authors.lastname: Zamudio
authors.forename: Luana
authors.initials: L
authors.lastname: Paulesu
authors.forename: Isabella
authors.initials: I
authors.lastname: Caniggia
mesh_terms: D000328:Adult; D000531:Altitude; D002824:Chorionic Villi / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D009924:Organ Culture Techniques; D010100:Oxygen / Q000502:physiology*; D010920:Placenta / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D010100:Oxygen