Deacetylase inhibitor trichostatin A down-regulates Foxp3 expression and reduces CD4+CD25+ regulatory T cells.
The forkhead transcription factor Foxp3 is essential for the development and function of CD4+CD25+ regulatory T (Treg) cells, which act to maintain immune tolerance and prevent autoimmunity. Lysine acetylation that is regulated by lysine acetyltransferases and lysine deacetylases plays an important role in gene transcription and protein function. Lysine deacetylase inhibitor trichostatin A (TSA) is reported to up-regulate Foxp3 expression and increase the generation of CD4+CD25+ Treg cells in vivo. In contrast, we found that TSA dramatically reduced the levels of Foxp3 mRNA and protein in vitro. Moreover, TSA enhanced the activity of the Foxp3 promoter but increased the decay of Foxp3 mRNA. Furthermore, administration of TSA significantly impaired the expression of Foxp3 and reduced the number of CD4+CD25+Foxp3+ Treg cells in C57BL/6J mice. Thus, our results show that TSA reduces the expression of Foxp3 through induction of mRNA degradation in vitro. Accordingly, TSA decreases Foxp3 expression and reduces the number of Treg cells in vivo. Our results are not in agreement with previous reports, which are discussed.
Liu
Zhijian
Z
Laboratory of B Cell and Autoantibody, Institute of Health Sciences, Shanghai Institutes for Biological Sciences & Shanghai JiaoTong University School of Medicine, Chinese Academy of Sciences, Shanghai 200025, China.
Zhang
Chenquan
C
Sun
Jian
J
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; C012589:trichostatin A