Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease

  • De Iudicibus S
  • Franca R
  • Martelossi S
 et al. 
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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.

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  • Sara De Iudicibus

  • Raffaella Franca

  • Stefano Martelossi

  • Alessandro Ventura

  • Giuliana Decorti

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