S-adenosyl-L-homocysteine hydrolase inactivation curtails ovalbumin-induced immune responses.
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)-gamma 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.
Fu
Yun-Feng
YF
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.
Wang
Jun-Xia
JX
Zhao
Yang
Y
Yang
Yang
Y
Tang
Wei
W
Ni
Jia
J
Zhu
Yi-Na
YN
Zhou
Ru
R
He
Pei-Lan
PL
Li
Chuan
C
Li
Xiao-Yu
XY
Yang
Yi-Fu
YF
Lawson
Brian R
BR
Zuo
Jian-Ping
JP
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology*; D012435:S-Adenosylhomocysteine / Q000378:metabolism
D002087:Butyrates; D016207:Cytokines; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; D010047:Ovalbumin; D012435:S-Adenosylhomocysteine; D043383:Adenosylhomocysteinase; D000225:Adenine