A novel tylophorine analog W-8 up-regulates forkhead boxP3 expression and ameliorates murine colitis.

Abstract

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.

• Authors: 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
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 93 Issue 1 Pg. 83-93 (Jan 2013) ISSN: 1938-3673 [Electronic] United States
• PMID: 23142729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Indolizines
• Phenanthrenes
• tylophorine

Topics

• Alkaloids (pharmacology)
• Animals
• Blotting, Western
• Colitis (immunology, metabolism)
• Disease Models, Animal
• Forkhead Transcription Factors (biosynthesis, drug effects)
• Indolizines (pharmacology)
• Lymphocyte Activation (drug effects, immunology)
• Mice
• Phenanthrenes (pharmacology)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• Up-Regulation