ATF3 is a negative regulator of inflammation in human fetal membranes
Ratana Lim1, Gillian Barker1, Stella Liong1
1Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Introduction:
Infection and inflammation stimulate pro-inflammatory cytokines, prostaglandins and matrix metalloproteinase (MMP)-9, which play a central role in myometrial contractions and rupture of fetal membranes. In human and mouse immune cells, activating transcription factor 3 (ATF3) is a negative regulator of inflammation. No studies have examined the role of ATF3 in human labour.
Methods:
Primary amnion cells were used to determine the effect of interleukin (IL)-1β and the bacterial product fibroblast-stimulating lipopeptide (fsl-1) on ATF3 expression, and the effect of ATF3 siRNA on pro-labour mediators. ATF3 expression was assessed in fetal membranes from non-labouring and labouring women at term and preterm, and after preterm pre-labour rupture of membranes (PPROM).
Results:
IL-1β and fsl-1 significantly increased ATF3 expression. Silencing ATF3 significantly increased IL-1β- or fsl-1-induced expression of pro-inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1 (MCP-1)); cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin PGF2α release; and MMP-9 expression. ATF3 expression was decreased in fetal membranes with term labour. There was no effect of preterm labour or PPROM on ATF3 expression.
Discussion:
ATF3 is a negative regulator of inflammation in human fetal membranes; in primary amnion cells, ATF3 expression is induced by IL-1β and fsl-1, and ATF3 silencing further exacerbates the inflammatory response when stimulated with these factors. Subsequently, ATF3 expression is decreased in fetal membranes after term labour and with preterm chorioamnionitis, conditions closely associated with inflammation and infection. Our data suggest that ATF3 may play a role in the terminal processes of human labour and delivery.
Insights
Activating transcription factor 3 (ATF3) reduces inflammation in fetal membranes during term labor. ATF3 levels decrease in term labor, suggesting its role in the final stages of childbirth and infection-related conditions.
Area of Science:
- Reproductive biology
- Immunology
- Molecular biology
Background:
- Infection and inflammation trigger pro-inflammatory mediators crucial for labor.
- Activating transcription factor 3 (ATF3) acts as a negative regulator of inflammation in immune cells.
- The role of ATF3 in human labor remains unexplored.
Purpose of the Study:
- To investigate the role of ATF3 in human labor and fetal membrane inflammation.
- To determine the effect of inflammatory stimuli on ATF3 expression in amnion cells.
- To assess ATF3 expression in fetal membranes during term and preterm labor.
Main Methods:
- Primary amnion cells were treated with IL-1β and fsl-1 to study ATF3 expression.
- ATF3 was silenced using siRNA to evaluate its impact on pro-labor mediators.
- ATF3 expression was analyzed in fetal membranes from laboring and non-laboring women.
Main Results:
- IL-1β and fsl-1 significantly upregulated ATF3 expression in amnion cells.
- ATF3 silencing amplified inflammatory responses, including cytokine and chemokine production, prostaglandin release, and MMP-9 expression.
- ATF3 expression was notably decreased in fetal membranes during term labor.
Conclusions:
- ATF3 functions as a negative regulator of inflammation in human fetal membranes.
- Decreased ATF3 expression in term labor suggests its involvement in labor's terminal phases.
- ATF3 may play a significant role in managing inflammation during human labor and delivery.
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