Uric acid induces trophoblast IL-1β production via the inflammasome: implications for the pathogenesis of preeclampsia

Am J Reprod Immunol. 2011 Jun;65(6):542-8. doi: 10.1111/j.1600-0897.2010.00960.x.

Abstract

Problem: Preeclampsia is associated with hyperuricemia, which correlates with the disease severity. Levels of circulating uric acid increase before the clinical manifestations, suggesting that they may be causally related. Uric acid, or monosodium urate (MSU), activates the Nod-like receptor, Nalp3, leading to inflammasome activation and IL-1β processing. Because preeclampsia is associated with placental immune⁄ inflammatory dysregulation, we sought to determine in the trophoblast, the presence of the Nalp3 inflammasome, and the effect of MSU on its activation.

Method of study: Isolated first- and third-trimester trophoblasts were assessed for expression of the inflammasome components, Nalp1, Nalp3, and ASC. First-trimester trophoblast cells were incubated with or without MSU, and after which, IL-1β secretion and processing and caspase-1 activation were determined.

Results: Trophoblast cells expressed Nalp1, Nalp3, and ASC under basal conditions. Following incubation with MSU, first-trimester trophoblast IL-1β secretion was upregulated. This correlated with increased expression levels of active IL-1β and active caspase-1. ASC knockdown reduced MSU-induced IL-1β secretion.

Conclusion: These findings demonstrate that uric acid activates the inflammasome in the trophoblast, leading to IL-1β production. This may provide a novel mechanism for the induction of inflammation at the maternal–fetal interface leading to placental dysfunction and adverse pregnancy outcome, including preeclampsia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism
  • Caspase 1 / immunology
  • Caspase 1 / metabolism
  • Cell Line
  • Cytoskeletal Proteins / immunology
  • Cytoskeletal Proteins / metabolism
  • Disease Progression
  • Enzyme Activation / drug effects
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Humans
  • Hyperuricemia
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Interleukin-1beta / metabolism*
  • Maternal-Fetal Relations
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pre-Eclampsia / blood
  • Pre-Eclampsia / immunology*
  • Pre-Eclampsia / physiopathology
  • Pregnancy
  • Trophoblasts / drug effects*
  • Trophoblasts / metabolism
  • Trophoblasts / pathology
  • Uric Acid / blood
  • Uric Acid / pharmacology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP1 protein, human
  • NLRP3 protein, human
  • PYCARD protein, human
  • Uric Acid
  • Caspase 1