Repeated lipopolysaccharide exposure leads to placental endotoxin tolerance.

PROBLEM: Placental infection induces increased levels of pro-inflammatory cytokines, which have been implicated in the pathogenesis of preterm 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 is to determine if 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, TNF-α. However, their production was significantly diminished with repeated LPS doses. Production of 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.

CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.