Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the -180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the -180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300. Increased expression of p-CREM correlated with decreased production of IL-2. The transcription of a reporter gene driven by the -180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.
Solomou
E E
EE
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Juang
Y T
YT
Gourley
M F
MF
Kammer
G M
GM
Tsokos
G C
GC
D020121:5' Untranslated Regions / Q000378:metabolism; D000328:Adult; D000368:Aged; D050882:CREB-Binding Protein; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051786:Cyclic AMP Response Element Modulator; D050882:CREB-Binding Protein; C494363:CREBBP protein, human