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: Qing-Li Wu, Yun-Feng Fu, Wen-Liang Zhou, Jun-Xia Wang, Yong-Hong Feng, Jing Liu, Jian-Yi Xu, Pei-Lan He, Ru Zhou, Wei Tang, Gui-Feng Wang, Yu Zhou, Yi-Fu Yang, Jian Ding, Xiao-Yu Li, Xiao-Ru Chen, Chong Yuan, Brian R Lawson, Jian-Ping Zuo
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 313 Issue 2 Pg. 705-11 (May 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15640397 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• B7-1 Antigen
• B7-2 Antigen
• Cd86 protein, mouse
• Enzyme Inhibitors
• Growth Inhibitors
• Immunosuppressive Agents
• Membrane Glycoproteins
• Adenosylhomocysteinase

Topics

• Adenosylhomocysteinase (antagonists & inhibitors, physiology)
• Animals
• Antigens, CD (biosynthesis, metabolism)
• B7-1 Antigen (biosynthesis, metabolism)
• B7-2 Antigen
• Cell Survival (drug effects, immunology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects, immunology)
• Enzyme Activation (drug effects, immunology)
• Enzyme Inhibitors (pharmacology)
• Female
• Growth Inhibitors (pharmacology)
• Immunosuppressive Agents (pharmacology)
• Lymphocyte Culture Test, Mixed
• Male
• Membrane Glycoproteins (biosynthesis, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL