Inhibition of S-Adenosyl-l-homocysteine Hydrolase Induces Immunosuppression
- 1 May 2005
- journal article
- research article
- Published by Elsevier in The Journal of Pharmacology and Experimental Therapeutics
- Vol. 313 (2) , 705-711
- https://doi.org/10.1124/jpet.104.080416
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 μM DZ2002, and decreases were also seen in IL-12 and tumor necrosis factor-α 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.This publication has 31 references indexed in Scilit:
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