Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung

Adcock, Ian M.; Cr, Brown; Shirasaki, Hiroki; Barnes, Peter J.

doi:10.1183/09031936.94.07122117

Cited by 50 publications

(18 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mukaida et al 1994;Scheinman et al 1995a;Adcock et al 1994;Brostjan et al 1996) and second, by induction of IκBα (Scheinman et al 1995b;Auphan et al 1995), an inhibitory protein that binds to NF-κB and prevents translocation of the cytosolic factor to the nucleus (Grimm and Baeuerle 1993;Roff et al 1996). Newly synthesized IκBα may also interact with nuclear NF-κB proteins, possibly related to the termination of transcription (Arenzana-Seisdedos et al 1995).…”

Section: Discussionmentioning

confidence: 95%

Induction of cyclooxygenase-2 by platelet-derived growth factor (PDGF) and its inhibition by dexamethasone are independent of NF-κB/IκB transcription factors

Goppelt‐Struebe

Rehm

Schaefers

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

Glucocorticoids are potent inhibitors of cyclooxygenase-2 (prostaglandin G/H synthase-2, COX-2) expression. The focus of this work was to investigate the molecular mechanisms, by which glucocorticoids interfere with platelet-derived growth factor (PDGF)-mediated induction of COX-2 with special emphasis on the role of the transcription factors NF-kappaB/IkappaB alpha. In rat renal mesangial cells, PDGF induced a rapid and transient increase of COX-2 mRNA and protein, which reached maximal levels after 1-2 and 4 h, respectively. The in vivo half-life of COX-2 mRNA, which was estimated to be less than 1 h, was reduced by dexamethasone. Kinetic studies and COX-2 promoter activity assays indicated that dexamethasone also interfered with COX-2 transcription. Inhibition of COX-2 induction by dexamethasone was abrogated by cycloheximide, an inhibitor of translation, indicating dependence on de novo protein synthesis. As a possible mediator of dexamethasone action, the NF-kappaB/IkappaB alpha system of transcription factors was investigated. Dexamethasone doubled IkappaB alpha protein levels within 1 h and reduced complex formation of nuclear NF-kappaB proteins with DNA. Newly synthesized IkappaB alpha may thus bind to NF-kappaB and interfere with gene activation. PDGF-induced signalling, however, barely affected the NF-kappaB/IkappaB alpha system: IkappaB alpha protein remained unaltered for 30 min after treatment of mesangial cells with PDGF and was only reduced by 30% after 1 h. Concomitantly, binding of NF-kappaB proteins to DNA, detected by electrophoretic mobility shift assays, was slightly increased by 30%. Furthermore, stably transfected COX-2 promoter constructs with and without the NF-KB binding site were comparably activated by PDGF (2.5-fold increase of luciferase activity). Taken together, these data indicate that although dexamethasone interferes with the NF-kappaB/IkappaB alpha system of transcription factors, this mechanism is not essential for the inhibition of PDGF-induced COX-2 expression.

show abstract

Section: Discussionmentioning

confidence: 95%

Induction of cyclooxygenase-2 by platelet-derived growth factor (PDGF) and its inhibition by dexamethasone are independent of NF-κB/IκB transcription factors

Goppelt‐Struebe

Rehm

Schaefers

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

show abstract

“…We have demonstrated the activation of AP-1 in human lung after stimulation with PMA, TNF-α and IL-1β [50,58] and in peripheral blood mononuclear cells after activation with PMA [48]. [57,59,60].…”

Section: Activator Protein-1mentioning

confidence: 89%

“…Oxidants activate NF-κB in a human epithelial lines, resulting in increased expression of iNOS [46] and exposure of animals to the oxidant ozone results in NF-κB expression in lung [47]. Exposure of human peripheral blood mononuclear cells, epithelial cells and lung tissue to proinflammatory cytokines results in a marked activation of NF-κB that may be prolonged [48][49][50]. Virus infections are common triggers of acute severe exacerbations of asthma and are thought to initiate a prolonged inflammatory response.…”

Section: Role In Asthmamentioning

confidence: 99%

Transcription factors and asthma

Barnes

Adcock²

1998

Eur Respir J

286

165

View full text Add to dashboard Cite

Asthma is characterized by the expression of multiple genes for inflammatory proteins, such as cytokines, enzymes, receptors and adhesion molecules. This is orchestrated by transcription factors, which are proteins that bind to the promoter regions of these genes and may be activated by inflammatory stimuli, such as cytokines. Several transcription factors are involved in asthmatic inflammation, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), nuclear factor of activated T-cells (NF-AT), cyclic AMP response element binding protein (CREB) and signal transduction-activated transcription factors (STAT). These transcription factors lead to coordinated expression of multiple inflammatory genes. There is increasing evidence that synergistic interaction of these transcription factors (e.g. NF-kappaB and AP-1) results in the optimal expression of particular genes, resulting in the specific inflammatory pattern seen in asthmatic airways. Transcription factors are a target for antiasthma therapy. Corticosteroids activate glucocorticoid receptors, which themselves are transcription factors, and interact with other transcription factors to inhibit their actions. The interaction between transcription factors may be important in amplifying and inhibiting the inflammatory process. Many transcription factors interact with a large co-activator molecule CREB-binding protein (CBP) that coordinates the activation of several transcription factors and controls transcription through the regulation of deoxyribonucleic acid coiling around histone residues in the chromatin structure. Understanding transcription factors in asthma has given new insights into the complex chronic inflammatory process, the mechanism of action of corticosteroids, and may lead to new approaches to therapy in the future.

show abstract

“…The majority of patients have normal plasma cortisol concentrations and do not suffer from adrenal insufficiency, suggesting that the metabolic and endocrine functions of endogenous glucocorticoids are unimpaired. The defect appears to be in the anti-inflammatory action of corticosteroids and, whereas there are usually no abnormalities in binding of glucocorticoids to glucocorticoid receptors, there is an impaired interaction between glucocorticoid receptors and deoxyribonucleic acid (DNA), which appears to be secondary to an abnormality between the glucocorticoid receptor and the transcription factor activator protein-1 (AP-1) [77,78]. Indeed, there is an increased basal and stimulated activation of AP-1 in these patients, suggesting that this transcription factor may consume glucocorticoid receptors via a direct protein-protein interaction, thus reducing the antiinflammatory effect of glucocorticoids.…”

Section: Corticosteroid-resistant Asthmamentioning

confidence: 99%

Difficult asthma

Barnes¹,

Woolcock²

1998

Eur Respir J

250

165

View full text Add to dashboard Cite

Asthma is usually easy to manage, but approximately 5% of patients are not controlled even on high doses of inhaled corticosteroids. It is important to assess these patients carefully in order to identify whether there are any correctable factors that may contribute to their poor control. It is critical to make a diagnosis of asthma and to exclude other airway diseases, particularly chronic obstructive pulmonary disease (COPD), and vocal cord dysfunction ("pseudo-asthma"). Poor adherence to therapy, particularly inhaled corticosteroids, is a common reason for a poor response. There may be unidentified exacerbating factors, including unrecognized allergens, occupational sensitizers, dietary additives, drugs, gastro-oesophageal reflux, upper airway disease, or other systemic diseases, that need to be identified and avoided or treated. Psychological factors may be important in some patients, but it is difficult to know whether these are causal or secondary to troublesome disease. Some patients have instability of their asthma, with resistant nocturnal asthma, premenstrual exacerbations or chaotic and unpredictable instability (brittle asthma). A few patients are completely resistant to corticosteroids, but more patients are relatively resistant and require relatively high doses of corticosteroids to control their symptoms (steroid-dependent). Some patients develop progressive loss of lung function, as in patients with COPD. Management of patients with difficult asthma should be supervised by a respiratory specialist and should involve careful assessment to confirm a diagnosis of asthma, identification and treatment of exacerbating factors, particularly allergens, and recording of peak expiratory flow patterns. A period of hospital admission may be the best way to assess and manage these patients. Treatment involves optimizing corticosteroids therapy, assessing additional controllers such as long-acting inhaled or subcutaneous beta2-agonists or subcutaneous, theophylline and antileukotrienes. In some patients, the use of immunosuppressive treatments may reduce steroid requirements, although these treatments are rarely effective and have side-effects. In the future, the nonsteroid anti-inflammatory treatments now in development may be useful in these patients.

show abstract

Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung

Cited by 50 publications

References 18 publications

Induction of cyclooxygenase-2 by platelet-derived growth factor (PDGF) and its inhibition by dexamethasone are independent of NF-κB/IκB transcription factors

Induction of cyclooxygenase-2 by platelet-derived growth factor (PDGF) and its inhibition by dexamethasone are independent of NF-κB/IκB transcription factors

Transcription factors and asthma

Difficult asthma

Contact Info

Product

Resources

About