title: An iminosugar N-pentafluorobenzyl-1-deoxynojirimycin as a novel potential immunosuppressant for the treatment of Th2-related diseases.
abstract: Increased levels of Th2 cytokine interleukin-4 (IL-4) have been reported to be involved in the pathogenesis of the parasite Schistosoma japonicum (S. japonicum) infection or detected in the serum of the causative agent of acquired immunodeficiency syndrome (AIDS) patients. This correlates with a worsened outcome of AIDS. The inhibition of a Th2 type response might aid in the treatment of these Th2-related diseases. Previously, we found that N-pentafluorobenzyl-1-deoxynojirimycin (5F-DNM), a new derivative of 1-deoxynojirimycin (DNM) (an inhibitor of the glycoprotein processing enzymes, glucosidase I and II), had specific inhibition effects on human CD4(+) T cells. In this study, we further found that 5F-DNM not only markedly inhibited in vitro IL-4 production from human PBMCs, CD4(+) T cells and mouse splenocytes but also strongly inhibited the production of IL-4 in splenocytes from a mouse model of S. japonicum infection. The numbers of S. japonicum worms were significantly decreased in vivo upon the treatment of mice with 5F-DNM. We demonstrated the mechanism of 5F-DNM effects on CD4(+) T cells acts via the inhibition of the IL-4/JAK1/STAT6 signaling pathway. Moreover, 5F-DNM was found to induce CD4 internalization (transfer from the cellular surface to the cytoplasm) in CD4(+) T cells and had no significant effects on the overall expression levels of CD4. These findings indicate that 5F-DNM might be used as a potential candidate for the treatment of S. japonicum parasitic infection, AIDS and other Th2-related diseases.
authors.affiliation: State key laboratory of Virology, Department of Immunology, and Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Donghu Road 165#, Wuhan 430071, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Shaoru
authors.initials: S
authors.lastname: Wang
authors.forename: Yi-Dan
authors.initials: YD
authors.lastname: Zhou
authors.forename: Tian
authors.initials: T
authors.lastname: Xiang
authors.forename: Huifen
authors.initials: H
authors.lastname: Dong
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Xiao-Lian
authors.initials: XL
authors.lastname: Zhang
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008956:Models, Chemical; D012549:Schistosoma japonicum / Q000378:metabolism; D012552:Schistosomiasis; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000187:drug effects*; D013997:Time Factors; D005464:Fluorobenzenes; D005466:Fluorocarbons
chemical_list: D017485:1-Deoxynojirimycin; D001593:Benzyl Compounds; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D015847:Interleukin-4; C495827:N-pentafluorobenzyl-1-deoxynojirimycin; D005464:Fluorobenzenes; D005466:Fluorocarbons