Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression

doi:10.1124/jpet.104.080416

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression
	Wu, QL ; Fu, YF ; Zhou, WL ; Wang, JX ; Feng, YH ; Liu, J; Xu, JY ; He, PL ; Zhou, R ; Tang, W
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2005-05
卷号	313 期号:2 页码:705-711
ISSN号	0022-3565
DOI	10.1124/jpet.104.080416
文献子类	Article
英文摘要	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 mu M 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.
WOS关键词	DIFFERENTIAL REGULATION ; INDUCED ARTHRITIS ; INTERFERON-GAMMA ; IFN-GAMMA ; IN-VITRO ; CELLS ; INTERLEUKIN-12 ; PROLIFERATION ; MACROPHAGES ; ADENOSYLHOMOCYSTEINE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000228357900026
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273881]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zuo, JP
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Lab Immunopharmacol, Shanghai 201203, Peoples R China 3.Gen Atom Co, Diazyme Labs Div, San Diego, CA USA
推荐引用方式 GB/T 7714	Wu, QL,Fu, YF,Zhou, WL,et al. Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2005,313(2):705-711.
APA	Wu, QL.,Fu, YF.,Zhou, WL.,Wang, JX.,Feng, YH.,...&Zuo, JP.(2005).Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,313(2),705-711.
MLA	Wu, QL,et al."Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 313.2(2005):705-711.