Dimethyl fumarate activates the prostaglandin EP2 receptor and stimulates cAMP signaling in human peripheral blood mononuclear cells

Sarah E. Fiedler, Amelia R. Kerns, Catherine Tsang, Vivian Tsang, Dennis Bourdette, Sonemany Salinthone

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Dimethyl fumarate (DMF) was recently approved by the FDA for the treatment of relapsing remitting MS. The pathology of MS is a result of both immune dysregulation and oxidative stress induced damage, and DMF is believed to have therapeutic effects on both of these processes. However, the mechanisms of action of DMF are not fully understood. To determine if DMF is able to activate signaling cascades that affect immune dysregulation, we treated human peripheral blood mononuclear cells with DMF. We discovered that DMF stimulates cyclic adenosine monophosphate (cAMP) production after 1 min treatment in vitro. cAMP is a small molecule second messenger that has been shown to modulate immune response. Using pharmacological inhibitors, we determined that adenylyl cyclase mediates DMF induced cAMP production; DMF activated the prostaglandin EP2 receptor to produce cAMP. This response was not due to increased endogenous production of prostaglandin E2 (PGE2), but was enhanced by addition of exogenous PGE2. Furthermore, we determined that the bioactive metabolite of DMF, monomethyl fumarate (MMF), also stimulates cAMP production. These novel findings suggest that DMF may provide protection against MS by inhibiting immune cell function via the cAMP signaling pathway.

Original languageEnglish (US)
Pages (from-to)19-24
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume475
Issue number1
DOIs
Publication statusPublished - Jun 17 2016

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Keywords

  • cAMP
  • Dimethyl fumarate
  • Fumaric acid
  • Hydroxycarboxylic acid receptor 2
  • Immunomodulation
  • Prostaglandin receptor

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

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