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

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

Mechanisms of leukocyte accumulation and activation in chorioamnionitis: interleukin 1 beta and tumor necrosis factor alpha enhance colony stimulating factor 2 expression in term decidua.

Chorioamnionitis is a major cause of prematurity as well as perinatal morbidity and mortality. The present study observed a marked increase in immunohistochemical staining for Colony Stimulating Factor 2 (CSF2; also known as granulocyte macrophage-colony stimulating factor), a potent neutrophil and macrophage chemoattractant and activator, in the decidua of patients with CAM compared with controls (n = 8; P = .001). To examine the regulation of this CSF2, cultured decidual cells primed with estradiol (E2) or E2 plus medroxyprogesterone acetate, were exposed to tumor necrosis factor-α or interleukin-1β and secreted CSF2 measured by ELISA. Levels of CSF2 in E2 plus MPA-treated cultures increased 18- and 245-fold following treatment with TNF or IL1B (n = 7, P < .05). Quantitative RT-PCR demonstrated parallel changes in mRNA levels. This study reveals that CSF2 is strongly expressed in decidua from patients with CAM and indicates TNF or IL1B as important regulators of CAM-related decidual leukocyte infiltration and activation

Multiple receptors for HLA-G on human natural killer cells

HLA-G is the putative natural killer (NK) cell inhibitory ligand expressed on the extravillous cytotrophoblast of the human placenta. Killing of the class I negative human B cell line 721.221 by NK cells is inhibited by the expression of HLA-G. This inhibition is dependent on a high level of HLA-G expression. In the present study, the nature of the receptors that mediate the inhibition has been studied with 140 NK cell lines from two donors and 246 NK clones from 5 donors by blocking the inhibition using monoclonal antibodies against the known NK inhibitory receptors: CD158a, CD158b, and CD94. Both CD94 and the two CD158 proteins can function as receptors, although the former clearly predominates. In many cases, a combination of antibodies to these receptors is required to achieve maximal reversal of inhibition. Moreover, in at least one-third of the NK cells that are inhibited by HLA-G, these antibodies alone or in combination do not reverse inhibition, strongly suggesting the existence of a third major unidentified receptor for HLA-G

CD1d and invariant NKT cells at the human maternal–fetal interface

Invariant CD1d-restricted natural killer T (iNKT) cells comprise a small, but significant, immunoregulatory T cell subset. Here, the presence of these cells and their CD1d ligand at the human maternal–fetal interface was investigated. Immunohistochemical staining of human decidua revealed the expression of CD1d on both villous and extravillous trophoblasts, the fetal cells that invade the maternal decidua. Decidual iNKT cells comprised 0.48% of the decidual CD3+ T cell population, a frequency 10 times greater than that seen in peripheral blood. Interestingly, decidual CD4+ iNKT cells exhibited a striking Th1-like bias (IFN-γ production), whereas peripheral blood CD4+ iNKT clones exhibited a Th2-like bias (IL-4 production). Moreover, compared to their peripheral blood counterparts, decidual iNKT clones were strongly polarized toward granulocyte/macrophage colony-stimulating factor production. The demonstration of CD1d expression on fetal trophoblasts together with the differential pattern of cytokine expression by decidual iNKT cells suggests that maternal iNKT cell interactions with CD1d expressed on invading fetal cells may play an immunoregulatory role at the maternal–fetal interface