title: Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response.
abstract: OBJECTIVE
  To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZB×NZW F1 (NZB/W F1) mice.
  
  
  METHODS
  Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg·kg(-1)·d(-1)) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study.
  
  
  RESULTS
  Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-β. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-β, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-κB signaling in splenocytes. DZ2002 (500 μmol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-α, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 μmol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system.
  
  
  CONCLUSIONS
  DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shi-jun
authors.initials: SJ
authors.lastname: He
authors.affiliation: Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ze-min
authors.initials: ZM
authors.lastname: Lin
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yan-wei
authors.initials: YW
authors.lastname: Wu
authors.affiliation: Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Bing-xin
authors.initials: BX
authors.lastname: Bai
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiao-qian
authors.initials: XQ
authors.lastname: Yang
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Pei-lan
authors.initials: PL
authors.lastname: He
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Feng-hua
authors.initials: FH
authors.lastname: Zhu
authors.affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: 1] Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: Zuo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D002087:Butyrates; D051193:Toll-Like Receptors; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; D000225:Adenine