The cyclic adenosine 5'-monophosphate response element modulator suppresses IL-2 production in stimulated T cells by a chromatin-dependent mechanism.
The production of IL-2 is tightly controlled by several transcription factors that bind to the IL-2 promoter. The cAMP response element modulator (CREM) is known to form complexes with CREB and bind to the -180 site of the IL-2 promoter in anergic and in systemic lupus erythematosus T cells. In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. Transfection of an antisense CREM plasmid into T cells blocked the expression and binding of CREM to the IL-2 promoter and the decrease of IL-2 production, which follows the early increase after T cell stimulation with CD3 and CD28. In addition, as assessed by chromatin immunoprecipitation experiments, antisense CREM prevented the binding of protein 300 and cAMP response element binding protein and promoted the acetylation of histones. Antisense CREM also enhanced the accessibility of the IL-2 promoter to endonucleases and prevented the condensation of chromatin in vivo. Our data suggest that upon T cell activation, CREM gradually replaces phosphorylated CREB at the -180 site of the IL-2 promoter. CREM, in turn, binds protein 300 and cAMP response element binding protein, but CREM is unable to activate its histone acetyltransferase activity, which results in condensation of chromatin and down-regulation of IL-2 production.
Tenbrock
Klaus
K
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Juang
Yuang-Taung
YT
Tolnay
Mate
M
Tsokos
George C
GC
D000123:Acetyltransferases / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000494:pharmacology; D017252:CD3 Complex / Q000494:pharmacology; D050882:CREB-Binding Protein; D011232:Chemical Precipitation; D002843:Chromatin / Q000378:metabolism / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015246:Deoxyribonuclease EcoRI / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements / Q000187:drug effects / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D017252:CD3 Complex; D002843:Chromatin; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; C100875:DNA methyltransferase SSe9I; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D015246:Deoxyribonuclease EcoRI; C027908:endodeoxyribonuclease DdeI; D015252:Deoxyribonucleases, Type II Site-Specific