title: Alkaline phosphatase protects lipopolysaccharide-induced early pregnancy defects in mice.
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.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Lei
authors.affiliation: College of Life Science, Northeast Agricultural University, Harbin, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Ni
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herington
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Reese
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Bibhash C
authors.initials: BC
authors.lastname: Paria
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D010064:Embryo Implantation; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D017403:In Situ Hybridization; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D000469:Alkaline Phosphatase