Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease

Abstract

Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn's disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity. However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormone-free GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient's specific genetic background, thus improving on efficacy and safety rates.

Role of the Long Non‐Coding RNA Growth Arrest‐Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease

“…Until now, different candidates of resistance have been identified in IBD patients [7], even though reported genetic associations have not yet shown consistent or robust results, and for most of them, results are controversial [7].…”

“…However, a considerable interindividual variability in GC response has been documented [4,5]: close to 20% of patients are resistant to these agents, while 40% of patients become dependent from GCs for maintaining clinical remission. Presently, there are no means to predict patients' response to GCs in advance [6,7].…”

“…However, a considerable interindividual variability in GC response has been documented [4,5]: close to 20% of patients are resistant to these agents, while 40% of patients become dependent from GCs for maintaining clinical remission. Presently, there are no means to predict patients' response to GCs in advance [6,7].GCs diffuse across the cell membrane and exert their biological effects primarily by binding to the cytoplasmic GC receptor (GR) [8,9], which translocates into the nucleus and interacts, through its DNA-binding domain (DBD) [10,11], with steroid-responsive genes promoter regions known as GC responsive elements (GREs) [12][13][14].Recent reports have shown that the growth arrest-specific 5 (GAS5) gene encodes for a long non-coding RNA (lncRNA) which can act as a riborepressor of the GR [15]. In particular, GAS5 exon 12-derived sequence has been shown to structurally mimic the GREs, preventing the binding of the activated GR complex to its target DNA sequences [16].…”

A Novel Strategy to Identify mRNA 3′ UTR and mRNA Level Difference in Crohn’s Disease

“…Since the 3′ UTR plays significant role in post-transcriptional regulation, different 3′ UTR lengths caused by alternative cleavage and polyadenylation (ApA) can lead to major difference in post-transcriptional binding site, such as binding sequence of miRNA. Several studies have demonstrated that shorter 3′ involved in multidrug resistance [22,23]. Alfreda et al found that 2 SNPs of ABCB1 (rs10248420 and rs2032583) were significantly related to CD, and 5 SNPs (rs1128503, rs1202184, rs1202186, rs2091766 and rs2235046) were associated with non-inflammatory CD based on a genotype-phenotype analysis [24].…”

A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function

“…Understanding how the GR interprets its ligands to permit appropriate cellular responses is of vital interest in both physiology and pharmacology, as the GR remains an important drug target in inflammation and malignancy (Barnes, 2011;De Iudicibus et al, 2011). The advent of drug design based on the crystal structure predicted pharmacophore has permitted new generations of ligands to be synthesised, including those studied here (Kauppi et al, 2003;Bledsoe et al, 2004).…”