QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.080416v1 313/2/705    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, Q.-L. Articles by Zuo, J.-P. Search for Related Content PubMed PubMed Citation Articles by Wu, Q.-L. Articles by Zuo, J.-P.

INFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibition of S-Adenosyl-L-homocysteine Hydrolase Induces Immunosuppression

Laboratory of Immunopharmacology and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China (Q.-L.W., Y.-F.F., W.-L.Z., J.-X.W., Y.-H.F., J.L., J.-Y.X., P.-L.H., R.Z., W.T., G.-F.W., Y.Z., Y.-F.Y., J.D., X.-Y.L., J.-P.Z.); and Diazyme Laboratories Division, General Atomics, San Diego, California (X.-R.C., C.Y., B.R.L.)

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 µM DZ2002, and decreases were also seen in IL-12 and tumor necrosis factor- 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.

Address correspondence to: Dr. Jian-Ping Zuo, Laboratory of Immunopharmacology and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China. E-mail: jpzuo{at}mail.shcnc.ac.cn

This article has been cited by other articles:

				B. R. Lawson, Y. Manenkova, J. Ahamed, X. Chen, J.-P. Zou, R. Baccala, A. N. Theofilopoulos, and C. Yuan Inhibition of Transmethylation Down-Regulates CD4 T Cell Activation and Curtails Development of Autoimmunity in a Model System J. Immunol., April 15, 2007; 178(8): 5366 - 5374. [Abstract] [Full Text] [PDF]

				Y.-F. Fu, Y.-N. Zhu, J. Ni, X.-G. Zhong, W. Tang, Y.-D. Re, L.-P. Shi, J. Wan, Y.-F. Yang, C. Yuan, et al. A Reversible S-Adenosyl-L-Homocysteine Hydrolase Inhibitor Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting T Cell Activation J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 799 - 808. [Abstract] [Full Text] [PDF]

				Y.-F. Fu, J.-X. Wang, Y. Zhao, Y. Yang, W. Tang, J. Ni, Y.-N. Zhu, R. Zhou, P.-L. He, C. Li, et al. S-Adenosyl-L-homocysteine Hydrolase Inactivation Curtails Ovalbumin-Induced Immune Responses J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1229 - 1237. [Abstract] [Full Text] [PDF]

				Y.-N. Zhu, W.-M. Zhao, Y.-F. Yang, Q.-F. Liu, Y. Zhou, J. Tian, J. Ni, Y.-F. Fu, X.-G. Zhong, W. Tang, et al. Periplocoside E, an Effective Compound from Periploca sepium Bge, Inhibited T Cell Activation in Vitro and in Vivo J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 662 - 669. [Abstract] [Full Text] [PDF]