title: Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1.
abstract: A mixture of different fumaric acid esters (FAE) is established for systemic therapy of psoriasis, a frequent inflammatory skin disease. The main active compound of FAE, however, has not been identified so far, and the mechanisms of activity are only partially understood. We analyzed the impact of FAE on in vitro immune function and aimed to gain knowledge about the mode of action. Dimethylfumarate (DMF) and diethylfumarate (DEF), but not fumaric acid, methylhydrogenfumarate and ethylhydrogenfumarate, exhibited potent depression of inflammatory cytokine secretion (e.g., tumor necrosis factoralpha, IL-12, and IFNgamma) in activated human peripheral blood mononuclear cells. Moreover, solely DMF and DEF inhibited alloreactive T-cell proliferation in mixed leukocyte reaction. Interestingly, these immunosuppressive effects were accompanied by the strong induction of the anti-inflammatory stress protein heme oxygenase 1 (HO-1). Supplementation with exogenous glutathione (GSH), which is known to bind DMF, prevented both HO-1 induction as well as the anti-inflammatory effects of DMF. Moreover, inhibition of HO-1 activity restored the diminished IL-12 and IFNgamma production after FAE treatment. These results suggest that DMF acts as active compound within the FAE mixture and at least partially mediates its immunomodulatory activity by the induction of the anti-inflammatory stress protein HO-1 ascribed to the functional depletion of reduced GSH.
authors.affiliation: CRBA Inflammation, Schering AG, Berlin, Germany.
authors.forename: Joachim C U
authors.initials: JC
authors.lastname: Lehmann
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Listopad
authors.forename: Christine U
authors.initials: CU
authors.lastname: Rentzsch
authors.forename: Frederik H
authors.initials: FH
authors.lastname: Igney
authors.forename: Arne
authors.initials: A
authors.lastname: von Bonin
authors.forename: Hartwig H
authors.initials: HH
authors.lastname: Hennekes
authors.forename: Khusru
authors.initials: K
authors.lastname: Asadullah
authors.forename: Wolf-Dietrich F
authors.initials: WD
authors.lastname: Docke
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D000069462:Dimethyl Fumarate; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D005650:Fumarates; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C035088:diethyl fumarate; D007371:Interferon-gamma; D051547:Heme Oxygenase-1; D000069462:Dimethyl Fumarate; D005978:Glutathione