title: Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression.
abstract: Lymphocytes depend on transmethylation reactions for efficient activation and function. These reactions are primarily catalyzed by S-adenosylmethionine-dependent methyltransferases, which convert S-adenosylmethionine to S-adenosyl-L-homocysteine. S-adenosyl-L-homocysteine is then hydrolyzed by S-adenosyl-L-homocysteine hydrolase to prevent feedback inhibition of transmethylation reactions. By impeding S-adenosyl-L-homocysteine hydrolase, a build-up of S-adenosyl-L-homocysteine occurs, and most intracellular transmethylation reactions cease. Thus, a nontoxic inhibitor of this enzyme might be a useful immunosuppressive therapeutic agent. We identified a potent reversible type III inhibitor of S-adenosyl-L-homocysteine hydrolase, DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate], and determined its cytotoxic and immunologic effects. We demonstrated that DZ2002 blocked S-adenosyl-L-homocysteine hydrolase more effectively than a type I inhibitor, but cytotoxicity from DZ2002 was greatly reduced. Although DZ2002 did not prevent concanavalin A-induced T cell proliferation or interleukin (IL)-2 production, it significantly reduced both a mixed lymphocyte reaction and IL-12 production from in vitro-stimulated splenocytes. In addition, levels of CD80 and CD86 on human monocytic THP-1 cells were decreased in a dose-dependent manner in the presence of 0.1 to 10 microM DZ2002, and decreases were also seen in IL-12 and tumor necrosis factor-alpha production from both mouse thioglycollate-stimulated peritoneal macrophages and THP-1 cells. In vivo, DZ2002 significantly suppressed a delayed-type hypersensitivity reaction as well as antibody secretion. We conclude that DZ2002's immunosuppressive effects are likely not solely attributed to T cell inhibition but also to the obstruction of macrophage activation and function through reductions in cytokine output and/or T cell costimulation. These data suggest an important dual role for the S-adenosyl-l-homocysteine hydrolase in both macrophage and T cell function.
authors.affiliation: Laboratory of Immunopharmacology and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Wu
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Fu
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Zhou
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Wang
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Feng
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Jian-Yi
authors.initials: JY
authors.lastname: Xu
authors.forename: Pei-Lan
authors.initials: PL
authors.lastname: He
authors.forename: Ru
authors.initials: R
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Gui-Feng
authors.initials: GF
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Li
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Chen
authors.forename: Chong
authors.initials: C
authors.lastname: Yuan
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zuo
mesh_terms: D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000378:metabolism; D051940:B7-2 Antigen; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D043383:Adenosylhomocysteinase