Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level.

Han, Jeong Soon; Brown, Torrey C.; Beutler, Bruce

doi:10.1084/jem.171.2.465

Cited by 463 publications

(292 citation statements)

References 20 publications

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“…It should be noted that although the increased expression of TNF-mRNA has been evident in the present study, this does not necessarily reflect changes in its protein levels, since its production is controlled at both transcriptional and posttranscriptional levels [2,3]. Nevertheless, there are studies showing increased TNF-activity or level in pre-eclamptic patients [11][12][13].…”

Section: Discussionmentioning

confidence: 59%

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Tumour necrosis factor-alpha (TNF-α) gene polymorphism and expression in pre-eclampsia

Chen

Wilson²,

Wang

et al. 1996

Clinical and Experimental Immunology

156

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SUMMARYPre-eclampsia is an endothelial disorder and TNF-has fundamental effects on endothelial cells by several means, including altering the balance between oxidant and anti-oxidant, changing the pattern of prostaglandin production and affecting expression of several cell surface components. To determine whether TNF-mRNA expression is increased in pre-eclamptic patients, leucocytes from pre-eclamptic patients, normal pregnant women and normal non-pregnant women were studied for TNF-expression using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Using a model of 373A ABI Sequencer, TNF-gene polymorphism was also analysed by GENESCAN and Genotyper software in order to explain the mechanism of abnormal TNF-expression. Our results show that TNFmRNA expression is significantly elevated in pre-eclamptic patients compared with the other two control groups. The high expression of TNF-may be associated with the TNF1 allele, whose frequency is markedly increased in pre-eclamptic patients. These observations are consistent with a major role for TNF-in mediating endothelial disturbances, and suggest a key role for TNF-in the development of pre-eclampsia.

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Section: Discussionmentioning

confidence: 59%

“…TNF-encoded by the TNF genes is a potent immunomodulator and an essential mediator of the inflammatory response. Its expression is induced by bacterial lipopolysaccharide (LPS), mitogens, and viruses and it is regulated both transcriptionally and post-transcriptionally [2,3].…”

Section: Introductionmentioning

confidence: 99%

Tumour necrosis factor-alpha (TNF-α) gene polymorphism and expression in pre-eclampsia

Chen

Wilson²,

Wang

et al. 1996

Clinical and Experimental Immunology

156

View full text Add to dashboard Cite

show abstract

“…The exact contribution of these processes will require further studies to measure transcriptional activity using nuclear run-on assays and to assess the course of mRNA degradation. The 3Ј-UTR of the TNF-␣ gene confers a similar translational repressive effect on TNF-␣ mRNA (27,50). Interestingly, although the translational repression caused by the TNF-␣ 3Ј-UTR is relieved by LPS (this study and Refs.…”

Section: Discusssionmentioning

confidence: 85%

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Németh¹,

Lutz²,

Csóka³

et al. 2005

The Journal of Immunology

244

161

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Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A1, A2A, A2B, and A3. Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3′-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3′-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3′-UTR of TNF-α mRNA. The IL-10 3′-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3′-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A2B receptor, because the order of potency of selective agonists was 5′-N-ethylcarboxamidoadenosine (NECA) > N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) > 2-chloro-N6-cyclopentyladenosine (CCPA) = 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.

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“…TNFα production is tightly controlled by both transcriptional and post-transcriptional mechanisms. The 3’untranslated region (UTR) of the TNFα mRNA has been found to contain AU-rich elements (AREs) that are important in the post-transcriptional regulation of TNFα mRNA [28] by controlling mRNA processing [29], mRNA stability [30] as well as translational inhibition [31]. The importance of the ARE in regulating TNFα production is underscored by studies demonstrating that mice lacking AREs in the 3’UTR exhibit enhanced TNFα production resulting in chronic inflammatory arthritis and Crohn’s-like inflammatory bowel disease [30].…”

Section: Introductionmentioning

confidence: 99%

Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level.

Cited by 463 publications

References 20 publications

Tumour necrosis factor-alpha (TNF-α) gene polymorphism and expression in pre-eclampsia

Tumour necrosis factor-alpha (TNF-α) gene polymorphism and expression in pre-eclampsia

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Mnk kinases in cytokine signaling and regulation of cytokine responses

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