Interleukin-1beta induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts

Mol Hum Reprod. 2003 Jan;9(1):1-8. doi: 10.1093/molehr/gag007.

Abstract

The aim of this study was to identify, in cultured human cervical fibroblasts, the mechanisms by which interleukin (IL)-1beta induces the synthesis of glycosaminoglycans (GAG) and to explore the putative role of prostaglandin E(2) (PGE(2)) in this process. Exposure of the cells for 24 h to IL-1beta induced a significant (P < 0.05) dose-dependent increase in GAG synthesis. IL-1beta (1 ng/ml) induced the expression of cyclooxygenase-2 (COX-2) protein 6 h after treatment, accompanied by a 7.5-fold increase in PGE(2) production. We confirmed that NS398, a selective COX-2 inhibitor, dose-dependently blocked PGE(2) augmentation following IL-1beta treatment. AH23848, the selective EP(4) receptor antagonist, completely abolished IL-1beta-induced GAG synthesis, whereas AH6809, an EP(2) receptor antagonist, had no effect on the stimulatory effects of IL-1beta. Furthermore, we demonstrated that 6 h exposure to IL-1beta induced a notable increase in EP(4) receptor mRNA expression and a decrease in EP(1) receptor mRNA but had no effect on the expression of EP(2) and EP(3) receptor transcripts. In conclusion, these findings indicate that IL-1beta not only induced GAG synthesis by increasing COX-2 protein expression and the subsequent PGE(2) production but also enhanced the responsiveness of cervical fibroblasts to PGE(2) by selectively up-regulating EP(4) receptor mRNA expression. These results suggest that PGE(2) may regulate human cervical ripening in an autocrine/paracrine manner via EP(4) receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Biphenyl Compounds / pharmacology
  • Cells, Cultured
  • Cervix Uteri / cytology*
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • DNA Primers
  • Dinoprostone / physiology*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Glycosaminoglycans / biosynthesis*
  • Humans
  • Interleukin-1 / pharmacology*
  • Isoenzymes / metabolism
  • Kinetics
  • Membrane Proteins
  • Nitrobenzenes / pharmacology
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • RNA, Messenger / genetics
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / genetics
  • Receptors, Prostaglandin E, EP1 Subtype
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP3 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Sulfonamides / pharmacology
  • Transcription, Genetic / drug effects

Substances

  • Biphenyl Compounds
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • DNA Primers
  • Glycosaminoglycans
  • Interleukin-1
  • Isoenzymes
  • Membrane Proteins
  • Nitrobenzenes
  • PTGER1 protein, human
  • PTGER2 protein, human
  • PTGER3 protein, human
  • PTGER4 protein, human
  • RNA, Messenger
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP3 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • AH 23848
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone