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Macrophage Migration Inhibitory Factor-Nitric Oxide Interaction in Human Fetal Membranes at Term Pregnancy

Carlo Ticconi, MD

Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy; Department of Surgery, Section of Gynecology and Obstetrics, University "Tor Vergata," Rome, Italy; Department of Physiology, Division of Immunoendocrinology and Reproductive Physiology, University of Siena, Siena, Italy; Department of Human Pathology and Oncology, University of Siena, Siena, Italy; ticconi{at}med.uniroma2.it

Francesca Ietta, PhD

Alessia Belmonte, MD

Nicoletta Bechi, PhD

Massimo Realacci, MD

Maura Di Vito, PhD

Felice Arcuri, PhD

Matteo Russo, PhD

Emilio Piccione, MD

Luana Paulesu, PhD

Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy; Department of Surgery, Section of Gynecology and Obstetrics, University "Tor Vergata," Rome, Italy; Department of Physiology, Division of Immunoendocrinology and Reproductive Physiology, University of Siena, Siena, Italy; Department of Human Pathology and Oncology, University of Siena, Siena, Italy

Objectives: Macrophage migration inhibitory factor (MIF), a multifunctional proinflammatory cytokine, has been recently involved in many aspects of reeproduction including pregnancy. However, no evidence is available on the role of MIF in gestational tissues nor on factors regulating MIF production. This study, conducted on explants of human fetal membranes at term gestation, has been undertaken to investigate whether: (1) MIF is produced by fetal membranes; (2) nitric oxide (NO) can regulate local MIF production; and (3) MIF, in turn, can influence NO release in these tissues.

Methods: Tissues were obtained from 56 healthy women who underwent elective cesarean delivery. Fetal membranes have been incubated with either sodium nitroprusside (NP), a NO donor, or recombinant MIF (r-MIF), or a specific anti-MIF antibody (MIF-Ab). Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, enzyme-linked immunosorbent assay (ELISA), and colorimetric assay have been used to detect MIF mRNA and protein, inducible nitric oxide synthase (iNOS), and NO metabolites.

Results: Fetal membranes basally express MIF mRNA and protein and release MIF. Exposing tissues to NP results in an increase of MIF mRNA expression and protein release. Conversely, treatment of tissues with MIF is followed by a reduction in iNOS mRNA and protein expression as well as in NO release. These effects are reversed by adding MIF-Ab.

Conclusions: MIF is generated and released by human fetal membranes at term. MIF mRNA and protein expression and release are modulated by NO. MIF, in turn, can reduce iNOS expression and NO release by these tissues. NO could be a regulator of MIF production in pregnancy and labor.

Key Words: Macrophage migration inhibitory factor • nitric oxide • fetal membranes • pregnancy

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