Cutting edge: TGF-beta-induced expression of Foxp3 in T cells is mediated through inactivation of ERK.
The peripheral induction of T regulatory cells can be accomplished by TGF-beta through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-beta-mediated action remains unclear. In the current study, we found that TGF-beta treatment of CD4+CD25- T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4+CD25- T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3+ T cells. Furthermore, treatment of T cells with either TGF-beta or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2'-deoxycytidine. These results indicate that the epigenetic regulation of TGF-beta-induced expression of Foxp3 may be mediated through the inactivation of ERK.
Luo
Xunrong
X
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Zhang
Qiang
Q
Liu
Victoria
V
Xia
Zhenbiao
Z
Pothoven
Kathryn L
KL
Lee
Chung
C
D000818:Animals; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D000097584:DNA Methyltransferase 3B
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051858:Forkhead Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011948:Receptors, Antigen, T-Cell; D053773:Transforming Growth Factor beta1; D000097584:DNA Methyltransferase 3B; C498833:Foxp3 protein, mouse