A novel tylophorine analog W-8 up-regulates forkhead boxP3 expression and ameliorates murine colitis.
J Leukoc Biol
; 93(1): 83-93, 2013 Jan.
Article
in En
| MEDLINE
| ID: mdl-23142729
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-ß-induced Foxp3 expression at the mRNA and the protein levels. Interestingly, W-8 synergistically increased the level of TGF-ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenanthrenes
/
Signal Transduction
/
T-Lymphocytes, Regulatory
/
Colitis
/
Alkaloids
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Forkhead Transcription Factors
/
Indolizines
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Leukoc Biol
Year:
2013
Document type:
Article