Received for publication November 9, 2004.
Revised December 8, 2004.
Accepted for publication January 5, 2005.

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 non-toxic 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, Methyl 4-(adenin-9-yl)- 2-hydroxybutanoate (DZ2002), 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 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 0.1-10 mM DZ2002 and, decreases were also seen in IL-12 and TNF-a 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.

Key words: 9-[(1'R, 2'S,3'R)-2',3'-dihydroxycyclopent-4'-en-1-yl]adenine, Cytokines, Delayed-type hypersensitivity, Immunosuppression, Methyl 4-(adenin-9-yl)-2-hydroxybutanoate, S-adenosyl-L-homocysteine hydrolase

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