Abstract
Excessive cytokine inflammatory response due to chronic or superphysiological level of microbial infection during pregnancy leads to pregnancy complications such as early pregnancy defects/loss and preterm birth. Bacterial toxin lipopolysaccharide (LPS), long recognized as a potent proinflammatory mediator, has been identified as a risk factor for pregnancy complications. Alkaline phosphatase (AP) isozymes have been shown to detoxify LPS by dephosphorylation. In this study, we examined the role of alkaline phosphatase (AP) in mitigating LPS-induced early pregnancy complications in mice. We found that 1) the uterus prior to implantation and implantation sites following embryo implantation produce LPS recognition and dephosphorylation molecules TLR4 and tissue non-specific AP (TNAP) isozyme, respectively; 2) uterine TNAP isozyme dephosphorylates LPS at its sites of production; 3) while LPS administration following embryo implantation elicits proinflammatory cytokine mRNA levels at the embryo implantation sites (EISs) and causes early pregnancy loss, dephosphorylated LPS neither triggers proinflammatory cytokine mRNA levels at the EISs nor induces pregnancy complications; 4) AP isozyme supplementation to accelerate LPS detoxification attenuates LPS-induced pregnancy complications following embryo implantation. These findings suggest that a LPS dephosphorylation strategy using AP isozyme may have a unique therapeutic potential to mitigate LPS- or Gram-negative bacteria-induced pregnancy complications in at-risk women.
Highlights
Clinical observations suggest that persistent or excessive inflammation from chronic, subclinical or inordinate infections of the female reproductive tissues or non-reproductive tissues are linked to an increased risk of developing general health problems and reproductive difficulties including infertility, spontaneous abortion, stillbirth and preterm birth (PTB) [1,2,3,4,5]
Localization of Cd14 and Tlr4 mRNAs using in situ hybridization in the pre-implantation uterus and post-implantation Embryo implantation sites (EISs)
We examined the localization of Cd14 and Tlr4 mRNAs to determine whether Cd14 and Tlr4 are expressed in similar uterine compartments
Summary
Clinical observations suggest that persistent or excessive inflammation from chronic, subclinical or inordinate infections of the female reproductive tissues or non-reproductive tissues are linked to an increased risk of developing general health problems and reproductive difficulties including infertility, spontaneous abortion, stillbirth and preterm birth (PTB) [1,2,3,4,5]. Previous studies have demonstrated that endometrial and decidual cells of women and mice express TLR4 and respond to LPS [20,21,22] and TLR4-MyD88 pathway promotes heightened inflammation in the uterus in response to LPS [23,24]. Despite these progresses in our understanding of the infection-induced inflammation response, maternal infection remains a major contributor of pregnancy complications and clinical therapies aimed at killing bacteria, suppressing inflammation or neutralizing the proinflammatory cytokine effects have proven ineffective in treating pregnant women with bacterial infection
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