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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Yun-Feng Fu, Yi-Na Zhu, Jia Ni, Xiang-Gen Zhong, Wei Tang, Yu-Dan Re, Li-Ping Shi, Jin Wan, Yi-Fu Yang, Chong Yuan, Fa-Jun Nan, Brian R. Lawson and Jian-Ping Zuo
Journal of Pharmacology and Experimental Therapeutics November 2006, 319 (2) 799-808; DOI: https://doi.org/10.1124/jpet.106.107185
Yun-Feng Fu
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Yi-Na Zhu
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Jia Ni
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Xiang-Gen Zhong
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Wei Tang
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Yu-Dan Re
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Li-Ping Shi
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Jin Wan
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Yi-Fu Yang
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Chong Yuan
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Fa-Jun Nan
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Brian R. Lawson
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Jian-Ping Zuo
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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

  • This work was supported by the Natural Science Research Foundation of China (Grant 30572195) and by the Shanghai Science and Technology Committee (Grant 03DZ19228)

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.107185.

  • 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.

  • ↵ Embedded Image 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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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Yun-Feng Fu, Yi-Na Zhu, Jia Ni, Xiang-Gen Zhong, Wei Tang, Yu-Dan Re, Li-Ping Shi, Jin Wan, Yi-Fu Yang, Chong Yuan, Fa-Jun Nan, Brian R. Lawson and Jian-Ping Zuo
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 799-808; DOI: https://doi.org/10.1124/jpet.106.107185

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Yun-Feng Fu, Yi-Na Zhu, Jia Ni, Xiang-Gen Zhong, Wei Tang, Yu-Dan Re, Li-Ping Shi, Jin Wan, Yi-Fu Yang, Chong Yuan, Fa-Jun Nan, Brian R. Lawson and Jian-Ping Zuo
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 799-808; DOI: https://doi.org/10.1124/jpet.106.107185
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