Mechanisms of Leukocyte Accumulation and Activation in Chorioamnionitis: Interleukin 1β and Tumor Necrosis Factor Α Enhance Colony Stimulating Factor 2 Expression in Term Decidua

Abstract

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 (E 2 ) or E 2 plus medroxyprogesterone acetate, were exposed to tumor necrosis factor-α or interleukin-1β and secreted CSF2 measured by ELISA. Levels of CSF2 in E 2 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.

Regulation of Interleukin-6 Expression in Human Decidual Cells and Its Potential Role in Chorioamnionitis

“…41 Moreover, inhibition of IL-6 expression by MPA in cultured term DCs described in the current study suggests a mechanism by which maintenance of high circulating progesterone levels blocks conversion of acute to chronic inflammation in the decidua. The specificity of this progestin-mediated inhibition of IL-6 expression is indicated by our observation that MPA did not affect expression of either GM-CSF, 40 M-CSF, 41 MCP-1, 42 or IL-8 29 by the DCs. The severe pathological complications associated with monocyte-associated chronic inflammation in the decidua described in the Alabama Preterm Birth Study were not experienced by the majority of patients with CAM in Figure 8.…”

“…These include GM-CSF, which is both a potent neutrophil and macrophage chemoattractant and activator, 40 as well as the monocyte/macrophage chemoattractant and activators, M-CSF 41 and monocyte chemoattractant protein-1 (MCP-1). 42 The decidua of patients with CAM-complicated pregnancies also contains several factors that can alter the immune response.…”

Progesterone inhibits in vitro fetal membrane weakening

“…MPA was chosen because it is known to be an effective inhibitor of TNF-induced GM-CSF production. 24 It metabolizes less rapidly in tissue culture than does progesterone. 27 HP was selected as a natural progestogen that has a strong affinity for the membranous progesterone receptor (mPR), [28][29][30][31][32] but not the nPR.…”

“…20,24 Decidual stromal cells have been shown to produce GM-CSF in response to TNF stimulation that is inhibited by MPA. 24 Our present findings confirm progestogen inhibition of TNF-induced GM-CSF production in choriodecidua by MPA.…”

“…23 In a previous study, we found that the progesterone analog medroxyprogesterone acetate (MPA) inhibited TNF-induced GM-CSF induction in decidual cells. 24 It thus seemed appropriate to hypothesize that progesterone would inhibit fetal membrane weakening by blocking GM-CSF production. However, GM-CSF is proposed to act, in part, by the activation of resident decidual mononuclear cells, which express membrane progesterone receptors.…”