Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT.

Paliogianni, Fotini; Raptis, Anastasios; Ahuja, Seema S.; Najjar, Sonia M.; Boumpas, Dimitrios T.

doi:10.1172/jci116353

Cited by 199 publications

(84 citation statements)

References 41 publications

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“…Dexamethasone seems to inhibit further signalling pathways induced by this kind of stimulation. The transcription of IL-2 is inhibited by dexamethasone via the inhibition of AP-1 (Paliogianni et al, 1993). Stimulation by a-CD28 has been reported to activate a CD28RE in the IL-2 promoter.…”

Section: Discussionmentioning

confidence: 99%

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Pahl

Zhang

Kuss³

et al. 2002

British J Pharmacology

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1 IL-13 is an important mediator in in¯ammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not wellcharacterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4 + T cells. 2 Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ ionomycin. However, stimulation by a-CD3/a-CD28 led to an enhanced IL-13 synthesis. 3 NF-kB inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more eectively after TPA/ionomycin stimulation. After a-CD3/a-CD28 stimulation, only 300 mM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally eective after a-CD3/a-CD28 and TPA/ionomycin stimulation. 4 p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very eectively, whereas a-CD3/a-CD28 stimulated IL-13 induction was resistant to this drug. 5 These results were con®rmed in puri®ed CD4 + T cells. In dierence to PBMCs a-CD3/a-CD28 stimulated IL-13 synthesis was eectively inhibited by CsA, FK-506 and U0126. 6 Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the ®rst time that inhibition of the MEK ± ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg 71 U0126 reduced lung eosinophilia in ovalbuminchallenged Brown Norway rats by 44%. 7 These results demonstrate that dierent signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.

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Section: Discussionmentioning

confidence: 99%

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Pahl

Zhang

Kuss³

et al. 2002

British J Pharmacology

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“…Exactly how signal transduction via CD40 occurs is unknown, but multiple pathways may be involved (43,44). CD40 ligation results in the activation of transcription factors including NF-B (31, 32), NF-AT (45), and AP-1 (46,47). However, the relative importance of these transcription factors as CD40 effectors is still unclear.…”

Section: Discussionmentioning

confidence: 99%

CD40 Engagement on Synovial Fibroblast Up-Regulates Production of Vascular Endothelial Growth Factor

Cho

Min

et al. 2000

The Journal of Immunology

107

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We tested the impact of CD40 engagement on the production of vascular endothelial growth factor (VEGF) from rheumatoid synovial fibroblasts. Fibroblast-like synovial cells (FLS) were prepared from the synovial tissues of rheumatoid arthritis patients and cultured in the presence of CD40 ligand-transfected (CD40L+) L cells. VEGF levels were determined in the culture supernatants by ELISA. Stimulation of FLS by CD40L+ L cells increased the production of VEGF by 4.1-fold over the constitutive levels of unstimulated FLS. The CD40L on activated T cells from rheumatoid synovial fluid also up-regulated VEGF production from FLS. Neither indomethacin nor Abs to IL-1β, TNF-α, and TGF-β did affect CD40L-induced VEGF production. Stimulation of FLS with TNF-α, IL-1β, and TGF-β increased VEGF production by 1.6-, 2.0-, and 5.2-fold, respectively, and displayed an additive effect on the production of VEGF by CD40L. VEGF mRNA expression was also up-regulated by the stimulation of FLS with membranes from the CD40L+ L cells. Dexamethasone completely abrogated CD40L-induced VEGF production. In addition, pyrrolidine dithiocarbamate partially down-regulated CD40L-induced VEGF production, showing that the NF-κB pathway was partly involved in the signaling of CD40L leading to VEGF production. Collectively, these results suggest that the interaction between CD40 on synovial fibroblasts and CD40L expressed on activated T lymphocytes may be directly involved in the neovascularization in rheumatoid synovitis by enhancing the production of VEGF.

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“…Regulation of the IL-2 gene occurs through a cooperative mechanism involving NF-AT and AP-1 interaction at the promoter. Inhibition by glucocorticoids involves disruption of this cooperativity (69) through the GR binding to AP-1 that disrupts binding to NF-AT (70). NF-AT and AP-1 can bind to the CLE0 element in the GM-CSF promoter (15).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Granulocyte-Macrophage Colony-Stimulating Factor Expression by Glucocorticoids Involves Inhibition of Enhancer Function by the Glucocorticoid Receptor Binding to Composite NF-AT/Activator Protein-1 Elements

Smith

Cousins

Jee

et al. 2001

The Journal of Immunology

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Increased expression of a number of cytokines including GM-CSF is associated with chronic inflammatory conditions such as bronchial asthma. Glucocorticoid therapy results in suppression of cytokine levels by a mechanism(s) not yet fully understood. We have examined regulation of GM-CSF expression by the synthetic glucocorticoid dexamethasone in human T cells. Transient transfection assays with reporter constructs revealed that dexamethasone inhibited the function of the GM-CSF enhancer, but had no effect on regulation of GM-CSF expression occurring through the proximal promoter. Activation of the GM-CSF enhancer involves cooperative interaction between the transcription factors NF-AT and AP-1. We demonstrate here that glucocorticoid-mediated inhibition of enhancer function involves glucocorticoid receptor (GR) binding to the NF-AT/AP-1 sites. These elements, which do not constitute recognizable glucocorticoid response elements, support binding of the GR, primarily as a dimer. This binding correlates with the ability of dexamethasone to inhibit enhancer activity of the NF-AT/AP-1 elements, suggesting a competition between NF-AT/AP-1 proteins and GR.

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Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT.

Cited by 199 publications

References 41 publications

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

CD40 Engagement on Synovial Fibroblast Up-Regulates Production of Vascular Endothelial Growth Factor

Suppression of Granulocyte-Macrophage Colony-Stimulating Factor Expression by Glucocorticoids Involves Inhibition of Enhancer Function by the Glucocorticoid Receptor Binding to Composite NF-AT/Activator Protein-1 Elements

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