Abstract
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.
Footnotes
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This work was supported by the Natural Science Research Foundation of China (Grant 30572195) and by the Shanghai Science and Technology Committee (Grant 03DZ19228)
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.107185.
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ABBREVIATIONS: EAE, experimental autoimmune encephalomyelitis; CNS, central nervous system; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; AdoHcy, S-adenosyl-l-homocysteine; IL, interleukin; DNFB, 2,4-dinitrofluorobenzene; Th1, type 1 helper T cell; IFN, interferon; DZ2002, methyl 4-(adenin-9-yl)-2-hydroxybutanoate; CFA, complete Freund's adjuvant; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; LN, lymph node; APC, antigen-presenting cell; CDK, cyclin-dependent kinase.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received May 2, 2006.
- Accepted August 15, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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