title: Sulforaphane protects from T cell-mediated autoimmune disease by inhibition of IL-23 and IL-12 in dendritic cells.
abstract: Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with anti-inflammatory properties. The published reports are best conceivable with an inhibition of T cell function, but the mode of action remains unknown. We therefore analyzed the effect of SFN on T cell-mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis. Disease amelioration was associated with reduced IL-17 and IFN-γ expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DCs) inhibited TLR4-induced IL-12 and IL-23 production, and severely suppressed Th1 and Th17 development of T cells primed by SFN-treated DCs. SFN regulated the activity of the TLR4-induced transcription factor NF-κB, without affecting the degradation of its inhibitor IκB-α. Instead, SFN treatment of DCs resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with and thereby inhibits NF-κB p65. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 activity at the IL23a and IL12b promoters. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS. Thus, our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting NF-κB p65-regulated IL-23 and IL-12 expression.
authors.affiliation: Department of Dermatology, University Medical Center, Eberhard Karls University Tübingen, 72076 Tübingen, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Geisel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brück
authors.forename: Ivana
authors.initials: I
authors.lastname: Glocova
authors.forename: Katja
authors.initials: K
authors.lastname: Dengler
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.forename: Oliver
authors.initials: O
authors.lastname: Rothfuss
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D016000:Cluster Analysis; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D013454:Sulfoxides; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D053759:Interleukin-23; D017879:Isothiocyanates; D016328:NF-kappa B; D013454:Sulfoxides; D018664:Interleukin-12; D004247:DNA; D051547:Heme Oxygenase-1; C016766:sulforaphane