Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth

J Biol Chem. 2016 Apr 8;291(15):8231-40. doi: 10.1074/jbc.M115.707836. Epub 2016 Feb 21.

Abstract

Recent studies provide evidence that premature maternal decidual senescence resulting from heightened mTORC1 signaling is a cause of preterm birth (PTB). We show here that mice devoid of fatty acid amide hydrolase (FAAH) with elevated levels ofN-arachidonyl ethanolamide (anandamide), a major endocannabinoid lipid mediator, were more susceptible to PTB upon lipopolysaccharide (LPS) challenge. Anandamide is degraded by FAAH and primarily works by activating two G-protein-coupled receptors CB1 and CB2, encoded by Cnr1 and Cnr2, respectively. We found thatFaah(-/-)decidual cells progressively underwent premature senescence as marked by increased senescence-associated β-galactosidase (SA-β-Gal) staining and γH2AX-positive decidual cells. Interestingly, increased endocannabinoid signaling activated MAPK p38, but not p42/44 or mTORC1 signaling, inFaah(-/-)deciduae, and inhibition of p38 halted premature decidual senescence. We further showed that treatment of a long-acting anandamide in wild-type mice at midgestation triggered premature decidual senescence utilizing CB1, since administration of a CB1 antagonist greatly reduced the rate of PTB inFaah(-/-)females exposed to LPS. These results provide evidence that endocannabinoid signaling is critical in regulating decidual senescence and parturition timing. This study identifies a previously unidentified pathway in decidual senescence, which is independent of mTORC1 signaling.

Keywords: anandamide (N-arachidonoylethanolamine) (AEA); cannabinoid receptor type 1 (CB1); fatty acid metabolism; pregnancy; senescence.

Publication types

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

MeSH terms

  • Amidohydrolases / genetics
  • Amidohydrolases / immunology
  • Animals
  • Arachidonic Acids / immunology*
  • Cells, Cultured
  • Decidua / cytology
  • Decidua / immunology
  • Endocannabinoids / immunology*
  • Female
  • Gene Deletion
  • Inflammation / complications*
  • Inflammation / genetics
  • Inflammation / immunology
  • Lipopolysaccharides / immunology
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Polyunsaturated Alkamides / immunology*
  • Premature Birth / etiology*
  • Premature Birth / genetics
  • Premature Birth / immunology*
  • Signal Transduction

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Lipopolysaccharides
  • Polyunsaturated Alkamides
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide