ATF2 impairs glucocorticoid receptor-mediated transactivation in human CD8+ T cells.
Chronic inflammatory diseases often have residual CD8(+) T-cell infiltration despite treatment with systemic corticosteroids, which suggests divergent steroid responses between CD4(+) and CD8(+) cells. To examine steroid sensitivity, dexamethasone (DEX)-induced histone H4 lysine 5 (K5) acetylation and glucocorticoid receptor alpha (GCR alpha) translocation were evaluated. DEX treatment for 6 hours significantly induced histone H4 K5 acetylation in normal CD4(+) cells (P = .001) but not in CD8(+) cells. DEX responses were functionally impaired in CD8(+) compared with CD4(+) cells when using mitogen-activated protein kinase phosphatase (1 hour; P = .02) and interleukin 10 mRNA (24 hours; P = .004) induction as a readout of steroid-induced transactivation. Normal DEX-induced GCR alpha nuclear translocation and no significant difference in GCR alpha and GCR beta mRNA expression were observed in both T-cell types. In addition, no significant difference in SRC-1, p300, or TIP60 expression was found. However, activating transcription factor-2 (ATF2) expression was significantly lower in CD8(+) compared with CD4(+) cells (P = .009). Importantly, inhibition of ATF2 expression by small interfering RNA in CD4(+) cells resulted in inhibition of DEX-induced transactivation in CD4(+) cells. The data indicate refractory steroid-induced transactivation but similar steroid-induced transrepression of CD8(+) cells compared with CD4(+) cells caused by decreased levels of the histone acetyltransferase ATF2.
Li
Ling-bo
LB
Divisions of Pediatric Allergy and Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Leung
Donald Y M
DY
Strand
Matthew J
MJ
Goleva
Elena
E
D000107:Acetylation / Q000187:drug effects; D051698:Activating Transcription Factor 2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D050881:E1A-Associated p300 Protein / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D051548:Histone Acetyltransferases / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000276:immunology / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D000074443:Lysine Acetyltransferase 5; D056920:Nuclear Receptor Coactivator 1; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000276:immunology; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects* / Q000276:immunology
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000893:Anti-Inflammatory Agents; D018797:Cell Cycle Proteins; D006657:Histones; C508609:IL10 protein, human; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D016753:Interleukin-10; D003907:Dexamethasone; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases