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Differential Regulation of Colony Stimulating Factor 1 and Macrophage Migration Inhibitory Factor Expression by Inflammatory Cytokines in Term Human Decidua: Implications for Macrophage Trafficking at the Fetal-Maternal Interface¹

Department of Human Pathology and Oncology,³ University of Siena, 53100 Siena, Italy Department of Obstetrics, Gynecology and Reproductive Sciences,⁴ Yale University School of Medicine, New Haven, Connecticut 06520 Department of Molecular and Cellular Biology,⁵ Harvard University, Cambridge, Massachusetts 02138

ABSTRACT

Macrophages are a major component of the leukocyte population of human pregnant endometrium. Although several crucial functions have been ascribed to these cells, the mechanisms underlying macrophage trafficking in the placental bed are poorly understood. The aim of this study was to evaluate the in vivo expression of two potentially antagonistic macrophage-targeting chemokines, colony stimulating factor 1 (CSF1, also known as M-CSF) and macrophage migration inhibitory factor (MIF), in term decidua, and to examine the effects of the inflammatory cytokines tumor necrosis factor (TNF, also known as TNF alpha) and interleukin 1beta (IL1B) on CSF1 and MIF expression in cultured decidual cells. The expression of CSF1 and MIF in term decidua was evaluated by immunohistochemistry. Cultured decidual cells were primed with estradiol (E₂) or with E₂ + medroxyprogesterone acetate (MPA), and then incubated with corresponding steroid(s) with or without TNF or IL1B. The levels of CSF1 and MIF protein and mRNA were assessed by ELISA and quantitative RT-PCR, respectively. Immunostaining for CSF1 and MIF was observed in term decidua. The levels of secreted CSF1 and MIF were similarly unchanged whether the decidual cells were incubated with E₂ or with E₂ + MPA. The CSF1 levels significantly increased in cultures exposed to E₂ or E₂ + MPA plus TNF or IL1B. In contrast, the MIF levels in TNF- and IL1B-treated cells were not changed significantly from the control cultures. The ELISA data were confirmed by quantitative RT-PCR analysis. These results indicate that CSF1 and MIF are involved in regulating macrophage trafficking at the fetal-maternal interface, and suggest a mechanism by which inflammatory cytokines influence pregnancy by regulating decidual macrophage infiltration.

cytokines, deciduas, immunology, pregnancy

¹This work was supported by grants from the National Institutes of Health 2 R01HD 33937-04 (C.J.L.) and 1 R01 HL070004-03 (C.J.L.), from the University of Siena (M.C. and F.A.), and from the Italian Ministry of Education and Scientific Research (P.T.).

Correspondence: ²Frederick Schatz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, Room 335 FMB P.O. Box 208063 New Haven, CT. FAX: 203 785 4713; e-mail: Frederick.Schatz{at}yale.edu

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