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INFLAMMATION AND IMMUNOPHARMACOLOGY

S-Adenosyl-L-homocysteine Hydrolase Inactivation Curtails Ovalbumin-Induced Immune Responses

Laboratory of Immunopharmacology and State Key Laboratory of Drug Research (Y.-F.F., J.-X.W., W.T., J.N., Y.-N.Z., R.Z., P.-L.H., X.-Y.L., Y.-F.Y., J.-P.Z.), Center for Drug Metabolism and Pharmacokinetics Research (Y.Z., C.L.), Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, People's Republic of China; Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China (Y.Y., J.-P.Z.); and Diazyme Laboratories Division General Atomics, San Diego, California (B.R.L.)

The reversible S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002) suppresses macrophage activation and function. The effects of DZ2002 on T cell function, however, are still unclear. Here, we examined whether DZ2002 alters type 1 helper T cell (Th1) and/or type 2 helper T cell (Th2) immune responses, and whether these effects are associated with both the inhibition of AdoHcy hydrolase and intracellular elevation of endogenous AdoHcy. Male C57BL/6 mice immunized with ovalbumin (OVA) were treated with DZ2002 (1, 5, and 25 mg/kg/day) after which lymphocyte proliferation, cytokine production, and IgG responses to OVA were monitored. Administration of DZ2002 dose dependently suppressed OVA-specific lymphocyte proliferation and anti-OVA IgG production compared with controls. Interleukin (IL)-2 and interferon (IFN)- as well as anti-OVA IgG2a and IgG3, indicators of Th1 immune responses, were markedly decreased in mice treated with DZ2002, whereas IL-4 and anti-OVA IgG1, indicators of Th2 immune responses, were only mildly suppressed. AdoHcy hydrolase activity in spleens of DZ2002-treated mice was substantially blocked, and not surprisingly, AdoHcy levels were significantly elevated compared with controls. Finally, similar immunosuppressive effects were also observed in mice treated with AdoHcy. These data strongly indicate that DZ2002 suppresses antigen-induced specific immune responses, particularly Th1 responses, through inhibition of AdoHcy hydrolase and elevation of endogenous AdoHcy.

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

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