Abstract
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.
MeSH terms
-
Animals
-
Cells, Cultured
-
DNA (Cytosine-5-)-Methyltransferase 1
-
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
-
DNA (Cytosine-5-)-Methyltransferases / biosynthesis
-
DNA Methylation
-
DNA Methyltransferase 3A
-
DNA Methyltransferase 3B
-
Down-Regulation / genetics
-
Down-Regulation / immunology
-
Enzyme Activation / immunology
-
Forkhead Transcription Factors / biosynthesis*
-
Gene Expression Regulation / immunology*
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred NOD
-
Mice, Transgenic
-
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Phosphorylation
-
Receptors, Antigen, T-Cell / physiology
-
Resting Phase, Cell Cycle / immunology
-
T-Lymphocytes, Regulatory / enzymology
-
T-Lymphocytes, Regulatory / immunology*
-
T-Lymphocytes, Regulatory / metabolism*
-
Transforming Growth Factor beta1 / physiology*
Substances
-
Forkhead Transcription Factors
-
Foxp3 protein, mouse
-
Receptors, Antigen, T-Cell
-
Transforming Growth Factor beta1
-
DNA (Cytosine-5-)-Methyltransferase 1
-
DNA (Cytosine-5-)-Methyltransferases
-
DNA Methyltransferase 3A
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3