Repeated lipopolysaccharide exposure leads to placental endotoxin tolerance

Abstract

Problem Placental infection induces increased levels of pro‐inflammatory cytokines, which have been implicated in the pathogenesis of pre‐term labor. Endotoxin tolerance is a phenomenon in which exposure to a dose of endotoxin makes tissue less responsive to subsequent exposures. The objective of our study was to determine whether repeated exposure to endotoxin will induce a tolerant phenotype in normal human second‐trimester placental tissue. Methods of study Human second‐trimester placental explants from elective termination of pregnancy were cultured and exposed to endotoxin (LPS). After 24 hours, the media was collected for analysis, and the explants were re‐exposed to LPS after adding fresh media for another 24 hours. This process was repeated for a total of 4 LPS doses. The media was collected from each day and analyzed for cytokine levels. Results The first LPS treatment stimulated the secretion of the pro‐inflammatory cytokines IL‐1β and TNF‐α. However, their production was significantly diminished with repeated LPS doses. Production of the anti‐inflammatory cytokines, IL‐1ra and IL‐10, was also stimulated by the first LPS treatment, but secretion was more gradually and moderately decreased with repeated LPS doses compared to the pro‐inflammatory cytokines. The ratios of the anti‐inflammatory/pro‐inflammatory mediators (IL‐1ra/IL‐1β and IL‐10/TNF‐α) indicate a progressively more anti‐inflammatory milieu with repeated LPS doses. Conclusion Repeated LPS exposure of human second‐trimester placental tissues induced endotoxin tolerance. We speculate that endotoxin tolerance at the maternal‐fetal interface will protect the fetus from exaggerated inflammatory responses after repeated infectious exposure.

SARS‐CoV‐2 prevalence and maternal‐perinatal outcomes among pregnant women admitted for delivery: Experience from COVID‐19‐dedicated maternity hospital in Jammu, Jammu and Kashmir (India)

“…47 Immunomodulatory changes in the placenta are accounted for adverse perinatal outcomes such as preterm birth, fetal growth restriction and even fetal death in case of SARS-CoV-2 positive pregnant women admitted for delivery. 6,48,49 Our results are in accordance with previous reports demonstrating that viral infections during pregnancy lead to higher rates of complications in fetuses including spontaneous abortion, premature birth, and intrauterine GUPTA ET AL.…”

MicroRNA-Mediated Control of Inflammation and Tolerance in Pregnancy

“…Our lab demonstrated that endotoxin tolerance exists in placental tissues (109) and we proposed a model of miRNA-mediated placental immune tolerance packaged within EVs. An LPS stimulus primes placental trophoblasts to exhibit a proinflammatory response through the TLR4 pathway, which activates NF-κB to increase pro-inflammatory cytokine expression and release (such as TNFα) (Figure 1).…”

Pre- and Post-Natal Endotoxin Exposures: Effects on Leucocyte Ratios and Levels of IL-1β, TNF-, Gonadotropins and Corticosterone in Female Rats

“…Therefore, it is might be possible that postnatal cytokine response does not occur if the dose administered in prenatal period is lower than 200 μg/kg. In a study conducted in humans, induction of second trimester placental tissue with endotoxin has been reported to provide tolerance to repeated ednotoxins (30).…”