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

Abstract

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-OVAIgG2a 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.

Inhibition of Transmethylation Down-Regulates CD4 T Cell Activation and Curtails Development of Autoimmunity in a Model System

“…For example, blockade of SAHase was associated with decreased Ig production and slower cell growth in a lymphoblastoid cell line (6) and decreased humoral and cellmediated immune responses (7)(8)(9)(10). Mice deficient in the arginine methyltransferase CARM1 showed a partial developmental arrest in an early thymocyte progenitor subset (11).…”

“…A major hurdle in this effort was the irreversible action of such compounds and associated severe toxicity (5). Recently, however, we developed a potent, but reversible, SAHase-inhibiting compound (methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002) and demonstrated its immunosuppressive activity (7,8). This compound was rationally designed based on the x-ray crystal structure of SAHase (13), and computational binding studies which compared an irreversible SAHase inhibitor that reduced enzyme-bound NAD ϩ to NADH with a reversible SAHase inhibitor (D-Eritadenine) that did not reduce NAD ϩ to NADH or alter the structure of SAHase.…”

Mineral pitch stimulates humoral, cellular and innate immune responses in mice

“…Considering the critical role of cytokines in determining IgG isotype switching, it is important to analyze if cytokine profile was in agreement with IgG subclass. Further, on the basis of the cytokine profile, CD4 þ T cells can be subdivided into Th1 and Th2 cells (Fu, 2006). The Th1 response supports protective immunity against intracellular infections such as those caused by viruses, bacteria, protozoa and cancer cells.…”

A ReversibleS-Adenosyl-l-Homocysteine Hydrolase Inhibitor Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting T Cell Activation

“…Spleens or draining lymph nodes (LNs) (axillary and inguinal) (n ϭ 10 mice/group) were removed, and cell suspensions were prepared as previously described with some modifications (Wu et al, 2005;Fu et al, 2006). Briefly, erythrocytes were lysed with Tris-NH 4 Cl.…”