A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation.
The reversible S-adenosyl-l-homocysteine hydrolase inhibitor DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate] suppresses antigen-induced-specific immune responses, particularly type 1 helper T cell (Th1)-type responses. Experimental autoimmune encephalomyelitis (EAE) is thought to be a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of human multiple sclerosis (MS). In this study, we examined the effects of DZ2002 on active EAE induced by myelin oligodendrocyte glycoprotein (MOG) 35-55 in female C57BL/6 mice. Administration of DZ2002 (50 mg/kg/day i.p.) significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG35-55-specific T cell proliferation and Th1-type cytokine production. In vitro studies also demonstrated that DZ2002 inhibited anti-CD3/28-induced naive T cell activation concomitant with the down-regulation of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D3, and the up-regulation or protection of the CDK inhibitor p27. These findings highlight the fact that DZ2002 likely prevents EAE by suppressing T cell activation and suggest its utility in the treatment of MS and other Th1-mediated inflammatory diseases.
Fu
Yun-Feng
YF
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
Zhu
Yi-Na
YN
Ni
Jia
J
Zhong
Xiang-Gen
XG
Tang
Wei
W
Re
Yu-Dan
YD
Shi
Li-Ping
LP
Wan
Jin
J
Yang
Yi-Fu
YF
Yuan
Chong
C
Nan
Fa-Jun
FJ
Lawson
Brian R
BR
Zuo
Jian-Ping
JP
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D002087:Butyrates / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D002087:Butyrates; D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; C445081:myelin oligodendrocyte glycoprotein (35-55); D043383:Adenosylhomocysteinase; D000225:Adenine