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A novel tylophorine analog W-8 up-regulates forkhead boxP3 expression and ameliorates murine colitis.
MedLine Citation:
PMID:  23142729     Owner:  NLM     Status:  Publisher    
Tylophorine and analogs are phenanthroindolizidine alkaloids, several of which have been reported to have anticancer, antiviral, and anti-inflammatory properties. However, their function in the immune system remains widely unknown. Transcription factor Foxp3 is critical for the development and function of Treg, which down-regulates the immune system and maintains tolerance to self-antigens. In the present study, we defined a novel tylophorine analog, W-8, enhanced TGF-β-induced Foxp3 expression at the mRNA and the protein levels. Interestingly, W-8 synergistically increased the level of TGF-β-induced p-Smad3 through inhibition of the AKT/mTOR pathway and enhanced the demethylation of the promoter region of the Foxp3 through inhibition of the ERK pathway and DNMT1 expression. Moreover, administration of W-8 suppressed TNBS-induced murine colitis and increased Tregs in lymphoid tissues. Finally, W-8 enhanced conversion of naïve T cells to Tregs in vivo. In summary, our results defined a novel compound that enhanced Foxp3 expression through transcriptional and epigenetic programs, and it might serve as a therapeutic agent for inflammatory diseases.
Xianyi Meng; Yun Zhang; Zhenghu Jia; Xiaojing Huo; Xiangjun He; Gaofei Tian; Meng Wu; Ziwen Wang; Xinglong Zhou; Sidong Xiong; Xiaoming Gao; Zhenzhou Wu; Jihong Han; Liqing Zhao; Puyue Wang; Zhangyong Hong; Qingmin Wang; Zhinan Yin
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-9
Journal Detail:
Title:  Journal of leukocyte biology     Volume:  -     ISSN:  1938-3673     ISO Abbreviation:  J. Leukoc. Biol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8405628     Medline TA:  J Leukoc Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
*State Key Laboratories of Medicinal Chemical Biology, College of Life Sciences, and.
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