Molecular Control of Immune/Inflammatory Responses: Interactions Between Nuclear Factor-κB and Steroid Receptor-Signaling Pathways

McKay, Lorraine I.; Cidlowski, John A.

doi:10.1210/edrv.20.4.0375

Cited by 365 publications

(234 citation statements)

References 237 publications

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“…NF-B antagonizes GR action through mutual protein-protein interactions by inhibiting its binding to GREs or by preventing the GRE-bound GR coactivator complex from effectively modulating transcription (23,24) (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

“…Action of FLASH on GR Is Independent of the NF-B Pathway-TNF␣ antagonizes the effects of glucocorticoids through activation of NR-B (23,34). Since TNF␣ induced FLASH nuclear localization and FLASH suppressed GR transactivation, we examined the relative contribution of FLASH on TNF␣-induced suppression of GR-induced, GRE-mediated transactivation by dissecting its activity from that of NF-B (Fig.…”

Section: Identification Of Flash As a Binding Partner Of Grip1 In Amentioning

confidence: 99%

“…NF-B is also stimulated by many inflammation-promoting substances, including other proinflammatory cytokines, endotoxins, intracellular proteins liberated from necrotic cells, oxygen radicals, and oxidized molecules (22). NF-B antagonizes GR action at several different steps, including direct interaction with it and interference with its transcriptional activity (23,24).…”

mentioning

confidence: 99%

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Tumor Necrosis Factor α Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators

Kino

Chrousos

2003

Journal of Biological Chemistry

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Tumor necrosis factor ␣ (TNF␣) and its downstream transcription factor nuclear factor B (NF-B) suppress glucocorticoid action, contributing to tissue resistance to glucocorticoids in several pathologic inflammatory states. p160 nuclear receptor coactivators on the other hand, contribute to the transcriptional signal of the glucocorticoid receptor (GR) through interaction with it via LXXLL motifs in their nuclear receptor-binding (NRB) domain. To discover TNF␣-induced factors that regulate GR activity at the coactivator level, we performed yeast two-hybrid screening using the NRB domain of the glucocorticoid receptor-interacting protein 1 (GRIP1) as bait. We found that FLICE-associated huge protein (FLASH), which transduces TNF␣ and Fas ligand signals, bound the NRB domain of GRIP1 at a region between the second and third LXXLL motifs. FLASH suppressed both GR transactivation and GRIP1 enhancement of the glucocorticoid signal and inhibited the physical interaction between GR and the GRIP1 NRB domain. Transfected green fluorescent proteinfused FLASH was located in both the cytoplasm and nucleus, while endogenous FLASH shifted its subcellular localization from the cytoplasm into the nucleus in response to TNF␣. FLASH antisense and super-repressor IB␣ inhibited the action of TNF␣ independently of each other and additively. These findings indicate that FLASH participates in TNF␣-induced blockade of GR transactivation at the nuclear receptor coactivator level, upstream and independently of NF-B.

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Flash As a Binding Partner Of Grip1 In Amentioning

confidence: 99%

mentioning

confidence: 99%

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Tumor Necrosis Factor α Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators

Kino

Chrousos

2003

Journal of Biological Chemistry

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“…pressive therapies known to block the development of neurological manifestations in this animal model. Given the critical role of CD4 ϩ T cells in EAE pathogenesis and the likely possibility that increases in glycolysis in the spinal cord reflected the accumulation of activated T lymphocytes, we used dexamethasone (DEX), a drug known to exert pleiotropic and potent immunosuppressive effects on T cells (35). Moreover, DEX has been previously shown to completely block EAE development in rodents (36).…”

Section: Eae-affected Mice Show Higher Uptake Of [ 18 F]fdg In the Spmentioning

confidence: 99%

Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis

Radu¹,

Shu²,

Shelly³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Upon ligand binding, the activated GR dissociates from the chaperone complex and translocates to the nucleus to activate or repress transcription of glucocorticoid target genes. Stimulation of gene transcription is mediated via binding of GR to glucocorticoid responsive elements (GREs) in the promoter region of glucocorticoid responsive genes (1)(2)(3).…”

mentioning

confidence: 99%

Steroid Responsiveness of Renal Epithelial Cells

Haij¹,

Adcock²,

Bakker³

et al. 2003

Journal of Biological Chemistry

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Glucocorticoids modulate cellular and inflammatory responses via stimulation or inhibition of gene transcription. Inhibition of cytokine gene expression is mediated via repression of transcription factors, including NF-B. Previously we have shown that cytokine production by renal epithelial cells is insensitive to the inhibitory action of dexamethasone. In this study we demonstrate that dexamethasone is unable to inhibit NF-B activation in the renal epithelial cell line HK-2, as measured by I B-␣ degradation and DNA binding activity. Transfection of an NF-B-inducible reporter gene demonstrated that non-stimulated HK-2 cells contain a high level of constitutively active NF-B compared with the steroid-sensitive airway epithelial cell line A549, which was not blocked by dexamethasone. Expression and nuclear translocation of the glucocorticoid receptor (GR) was comparable in both cell types. In HK-2 cells, dexamethasone stimulated expression of two glucocorticoidresponsive genes, ␤ 2 -adrenoreceptors and angiotensinogen. The capacity of GR to transactivate the native angiotensinogen glucocorticoid-responsive element (GRE) using chromatin-IP was not impaired. Moreover, dexamethasone activation of a GRE-driven reporter construct appeared to be equally effective, although less sensitive compared with A549 cells. In conclusion, we provide evidence that glucocorticoids are unable to repress the activity of NF-B in renal epithelial cells in the presence of an intact stimulatory pathway.

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Molecular Control of Immune/Inflammatory Responses: Interactions Between Nuclear Factor-κB and Steroid Receptor-Signaling Pathways

Cited by 365 publications

References 237 publications

Tumor Necrosis Factor α Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators

Tumor Necrosis Factor α Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators

Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis

Steroid Responsiveness of Renal Epithelial Cells

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