Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes.
IL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions.
From the Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Patras, Patras GR-26500, Greece and.
Ioannis
I
Panagoulias
From the Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Patras, Patras GR-26500, Greece and.
Tassos
T
Georgakopoulos
From the Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Patras, Patras GR-26500, Greece and.
Ioanna
I
Aggeletopoulou
the Institute of Molecular Biology, Genetics and Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens GR-11527, Greece.
Marios
M
Agelopoulos
the Institute of Molecular Biology, Genetics and Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens GR-11527, Greece.
Dimitris
D
Thanos
From the Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Patras, Patras GR-26500, Greece and mouzaki@upatras.gr.
Athanasia
A
Mouzaki
D000328:Adult; D016207:Cytokines; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D011401:Promoter Regions, Genetic / Q000235:genetics; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D016207:Cytokines; C494069:ETS2 protein, human; D007376:Interleukin-2; D050787:Proto-Oncogene Protein c-ets-2; D011948:Receptors, Antigen, T-Cell
T helper cells; human; interleukin; transcription regulation; transcription repressor