Corticosteroid effects on cell signalling

Abstract

Corticosteroids are the most effective anti-inflammatory therapy for asthma. Inflammation in asthma is characterised by the increased expression of multiple inflammatory genes regulated by pro-inflammatory transcription factors, such as nuclear factor-kB and activator protein-1, which bind to and activate coactivator molecules that acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways, mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase 2 to the activated transcription complex.Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes in order to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase-1, which inhibits mitogen-activated protein kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side-effects.In some patients with steroid-resistant asthma, there are abnormalities in glucocorticoid receptor signalling pathways. In chronic obstructive pulmonary disease patients and asthmatic patients who smoke, histone deacetylase 2 is markedly impaired as a result of oxidative/nitrative stress, and so inflammation is resistant to the anti-inflammatory effects of corticosteroids.The therapeutic implications of these new findings are discussed.

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

“…Anecdotally, the use of α-3 omega fatty acids (eicosapentaenoic acid) [52] and thalidomide (potent anti-TNF activity) have been reported [48]. Experimentally, glucocorticoids, aspirin [63], indomethacin [35,79], methotrexate [60], and celecoxib [23], all have been shown to have some efficacy, which are believed to be effective, in part, due to their ability to inhibit NF-ĸB activity [10,32,73,78]. However, these agents are neither potent nor selective for the NF-ĸB pathway.…”

“…However, it is possible that the protective effects of NBD may be indirect, due to its inhibition of the tumor growth itself. This is an important point to make because the dysregulation of NF-ĸB signaling is a major driver of cancer [53] and its inhibition has been shown experimentally to prevent oncogenic initiation and progression [10]. However, the magnitude between the tumor size inhibition (~30%, Supplemental Figure 1) and the skeletal muscle protection (~5%, Figure 2) are mismatched, suggesting that inhibition at the skeletal muscle may be prominent, although both mechanisms may be in play in the model tested.…”

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

“…Fifth, at least in the present rodent models it seems uncertain whether a major part of the anti-inflammatory effects of steroids is to be explained by their recruiting HDAC isoenzymes to the sites of pro-inflammatory gene transcription as it has been proposed [9]. Despite the fact that the pattern of H4K8 acetylation changed as expected in the presence of TSA and dexamethasone (Fig.…”

“…With respect to inflammation, it was posited that inhibition of HDAC isoenzymes (in particular HDAC2) increases histone acetylation in the vicinity of pro-inflammatory genes thus furthering pro-inflammatory gene expression [5,6]. Together with the fact that histone deacetylation was found to be decreased in steroid-resistant COPD and asthma patients [7,8], this led to the hypothesis that steroid resistance may be related to compromised HDAC activity [9].…”

Immunobiochemical Study of Host During Malaria Infection via Nitric Oxide Pathway after Modulation by Lipopolysaccharide and Dexamethasone in Mice Model

“…Glucocorticoids are potent drugs that can be used widely inflammatory disorders such asasthma, allergies, infections, autoimmune diseases (Rhen and Cidlowski, 2005). They have spread rapidly in the circulatory system and when they are passing through the cell membrane they will bind themselves to cytoplasmic receptors which cause regulated transcription for some genes that disabled such as inflammatory cytokines and enzymes including NOS (Barnes et al, 2006).…”