Transcription factors and asthma

Abstract

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.

Bronchial angiogenesis in severe glucocorticoid-dependent asthma

“…However, functional antagonism between the glucocorticoid receptor and NF-kB has also been described in the transcriptional regulation of genes encoding for IL-8 and ICAM-1 [30], which has been shown in this and a previous study [31] to be insufficiently downregulated in severe asthma. Although the effect of glucocorticoids on adhesion molecule expression was not specifically addressed in this study, the results suggest that the mode of action of glucocorticoid varies significantly, depending on the target gene.…”

“…The consistent decrease in numbers of vessels expressing E-selectin found in severe asthma relative to mild disease may possibly be due to the inhibitory effects of high doses of glucocorticoids [25], involving nuclear factor (NF)-kB inhibition [30]. However, functional antagonism between the glucocorticoid receptor and NF-kB has also been described in the transcriptional regulation of genes encoding for IL-8 and ICAM-1 [30], which has been shown in this and a previous study [31] to be insufficiently downregulated in severe asthma.…”

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

“…In hyperoxia, increased NF-κB activation is one of the first pulmonary responses upon exposure, and this activation occurs before the detection of any proinflammatory cytokine increases [74,[138][139][140][141]. The NF-κB-binding motif is present in the promoter regions of many genes that encode proinflammatory cytokines [81,[142][143][144]. Studies show that the presence of an active NF-κB site in the IL-8 promoter is essential for hyperoxiainduced IL-8 secretion from U937 macrophages [145].…”

The synergistic anti-asthmatic effects of glycyrrhizin and salbutamol

“…In asthma NF-κB is markedly activated, which in turn regulates many inflammatory genes that are abnormally expressed [17] . In the NF-κB pathway, TNF-α activates I-κB kinases, which induces the subsequent degradation of I-κBα.…”