title: 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.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xianyi
authors.initials: X
authors.lastname: Meng
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhenghu
authors.initials: Z
authors.lastname: Jia
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huo
authors.forename: Xiangjun
authors.initials: X
authors.lastname: He
authors.forename: Gaofei
authors.initials: G
authors.lastname: Tian
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.forename: Ziwen
authors.initials: Z
authors.lastname: Wang
authors.forename: Xinglong
authors.initials: X
authors.lastname: Zhou
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Gao
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Wu
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhao
authors.forename: Puyue
authors.initials: P
authors.lastname: Wang
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Hong
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects; D007212:Indolizines / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000470:Alkaloids; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007212:Indolizines; D010616:Phenanthrenes; C004218:tylophorine