title: Critical role of transmethylation in TLR signaling and systemic lupus erythematosus.
abstract: Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4(+) T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Fas(lpr) mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Tardif
authors.forename: Yulia
authors.initials: Y
authors.lastname: Manenkova
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zuo
authors.forename: Chong
authors.initials: C
authors.lastname: Yuan
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D002087:Butyrates / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D002087:Butyrates; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D051193:Toll-Like Receptors; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; D000225:Adenine