Prostaglandin E2 receptors of the EP2 and EP4 subtypes downregulate tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human gingival fibroblasts

J Periodontal Res. 1999 Nov;34(8):478-85. doi: 10.1111/j.1600-0765.1999.tb02284.x.


Prostaglandin E2 (PGE2) exerts its biological actions via EP receptors, which are divided into 4 subtypes of EP1, EP2, EP3 and EP4. In the present study, we investigated whether PGE2 regulated intercellular adhesion molecule-1 (ICAM-1) expression in human gingival fibroblasts (HGF) stimulated with tumor necrosis factor-alpha (TNF alpha) and if so, which subtype(s) of PGE2 receptors was involved. Exogenous addition of PGE2 to HGF inhibited ICAM-1 expression elicited by TNF alpha in a concentration-dependent manner. Treatment of HGF with indomethacin, a cyclo-oxygenase inhibitor, had no effect on TNF alpha-elicited ICAM-1 expression, although indomethacin completely inhibited PGE2 production enhanced by TNF alpha. Next, we examined which subtype(s) of the 4 EP receptors modulated the ICAM-1 expression elicited by TNF alpha, using subtype-specific agonists and antagonists. 11-deoxy-PGE1, a selective EP2/EP4 agonist, inhibited TNF alpha-elicited ICAM-1 expression as potently as PGE2, while butaprost, a selective EP2 agonist, was somewhat less effective than PGE2. AH23848B, an EP4 antagonist, antagonized the inhibitory effect of TNF alpha-elicited ICAM-1 expression by PGE2. Sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, were inert to TNF alpha-elicited ICAM-1 expression. As EP2 and EP4 receptors are linked to elevation of intracellular cyclic AMP (cAMP), the effect of dibutyryl cAMP and 8-bromo-cAMP, cAMP analogs, on TNF alpha-elicited ICAM-1 expression was examined. Both the agents downregulated ICAM-1 expression in TNF alpha-stimulated HGF. From these data, we suggest that PGE2 downregulates TNF alpha-induced ICAM-1 expression in HGF, via EP2 and EP4 receptors by cAMP-dependent signaling pathways, which may result in control of inflammatory and immunological responses in periodontal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Cell Culture Techniques / methods
  • Cells, Cultured
  • Dinoprostone / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / physiology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gingiva / cytology
  • Gingiva / drug effects
  • Gingiva / metabolism*
  • Humans
  • Immunohistochemistry
  • Intercellular Adhesion Molecule-1 / drug effects
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Receptors, Prostaglandin E / drug effects
  • Receptors, Prostaglandin E / metabolism*
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Stimulation, Chemical
  • Time Factors
  • Tumor Necrosis Factor-alpha / pharmacology*


  • PTGER2 protein, human
  • PTGER4 protein, human
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Dinoprostone