Post-transcriptional Regulation of Glucocorticoid Function
Glucocorticoids (GCs) are corticosteroid hormones critically involved in the homeostatic control of stress and immune responses. Endogenous GCs generally tend to support the innate immune responses while inhibiting overexpressed adaptive immune responses.
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Faoud T. Ishmael and Cristiana Stellato
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Post-transcriptional Gene Regulation in Inflammation as Target of GC Anti-inflammatory Action Mechanisms of PTR in Inflammation: Rationale for Therapeutic Anti-inflammatory Targeting
Post-transcriptional gene regulation (PTR) is a critical control mechanism of the inflammatory response integrated with transcriptional control of gene expression. By implementing changes in mRNA turnover and translation rates, PTR mechanisms adapt the amplitude and timing of protein expression to endogenous or environmental changes (Stoecklin and Anderson 2006a; Hollams et al. 2002). Transcriptional and post-transcriptional regulation are coordinately mediated by common signaling pathways—chiefly MAP kinases (Winzen et al. 1999; Frevel et al. 2003; Gaestel 2006; Gao et al. 2013). Rapid mRNA transcript degradation of cytokines, chemokines, enzymes and other mediators contribute to successful
F.T. Ishmael Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Section of Allergy and Immunology, The Pennsylvania State University Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA C. Stellato, MD, PhD (*) Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, Baronissi, SA 84081, Italy Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD, USA e-mail: [email protected] © Springer International Publishing Switzerland 2016 K.M.J. Menon, A.C. Goldstrohm (eds.), Post-transcriptional Mechanisms in Endocrine Regulation, DOI 10.1007/978-3-319-25124-0_13
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F.T. Ishmael and C. Stellato
cessation of an acute inflammatory reaction; conversely, aberrant stabilization of the targeted transcripts can support overexpression of inflammatory genes during chronic inflammation. Stress- and inflammation-driven signals can also rapidly adapt protein translation rates to changing extracellular environment (Stoecklin and Anderson 2006a; Hollams et al. 2002). Genome-wide studies indicate that up to 50 % of genes induced during a stress response are mainly regulated posttranscriptionally (Fan et al. 2002). RNA-binding proteins (RBP), microRNA (miRNA) and other classes of small noncoding RNAs (sncRNA) constitute the heterogeneous group of regulatory factors conveying PTR through binding to conserved sequences mainly present in the untranslated regions (UTR) of their mRNA targets, with which they form ribonucleoprotein (RNP) complexes ultimately conveying PTR action. The activation of regulatory factors and their assembly in multimeric RNP complexes is a dynamic process susceptible of regulation by inflammatory signaling (Winzen et al. 1999; Frevel et al. 2003; Gaestel 2006; Gao et al. 2013) and therefore, potentially amenable to therapeutic targeting. Small variations in mRNA half-life, in the range of two- to fourfold changes, can rapidly lead to over a 1000-fold difference in mRNA levels (Ross 1995). With additional regulation at the level of protein translation,
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