title: Dimethyl fumarate activates the prostaglandin EP2 receptor and stimulates cAMP signaling in human peripheral blood mononuclear cells.
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.
authors.affiliation: VA Portland Health Care System, Research and Development Service, 3710 SW US Veterans' Hospital Rd., Portland, OR 97239, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Fiedler
authors.affiliation: VA Portland Health Care System, Research and Development Service, 3710 SW US Veterans' Hospital Rd., Portland, OR 97239, USA.
authors.forename: Amelia R
authors.initials: AR
authors.lastname: Kerns
authors.affiliation: VA Portland Health Care System, Research and Development Service, 3710 SW US Veterans' Hospital Rd., Portland, OR 97239, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tsang
authors.affiliation: VA Portland Health Care System, Research and Development Service, 3710 SW US Veterans' Hospital Rd., Portland, OR 97239, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Tsang
authors.affiliation: VA Portland Health Care System, Research and Development Service, 3710 SW US Veterans' Hospital Rd., Portland, OR 97239, USA; Department of Neurology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
authors.affiliation: VA Portland Health Care System, Research and Development Service, 3710 SW US Veterans' Hospital Rd., Portland, OR 97239, USA; Department of Neurology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA. Electronic address: salintho@ohsu.edu.
authors.forename: Sonemany
authors.initials: S
authors.lastname: Salinthone
mesh_terms: D000262:Adenylyl Cyclases / Q000276:immunology; D000242:Cyclic AMP / Q000276:immunology*; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D015232:Dinoprostone / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007166:Immunosuppressive Agents; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000069462:Dimethyl Fumarate; D015232:Dinoprostone
keywords: Dimethyl fumarate; Fumaric acid; Hydroxycarboxylic acid receptor 2; Immunomodulation; Prostaglandin receptor; cAMP