Non-genomic Effects of Glucocorticoids: An Updated View.

Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs 'rapidly' enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and (ii) the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index.

[1]  J. Liao,et al.  Nontranscriptional actions of the glucocorticoid receptor , 2003, Journal of Molecular Medicine.

[2]  M. Lisanti,et al.  The caveolin proteins , 2004, Genome Biology.

[3]  J. Ruppersberg,et al.  Gene expression of P2X-receptors in the developing inner ear of the rat , 1999, Neuroscience Letters.

[4]  Thomas M Price,et al.  Actions of steroids in mitochondria. , 2007, Seminars in reproductive medicine.

[5]  C. Sekeris,et al.  Import of the glucocorticoid receptor into rat liver mitochondria in vivo and in vitro , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  R. Flower,et al.  Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor‐dependent, transcription‐independent mechanism , 2000, British journal of pharmacology.

[7]  G. Panayotou,et al.  Interaction of mitochondrial thioredoxin with glucocorticoid receptor and NF-kappaB modulates glucocorticoid receptor and NF-kappaB signalling in HEK-293 cells. , 2009, The Biochemical journal.

[8]  Anja M. Billing,et al.  Membrane Glucocorticoid Receptor Activation Induces Proteomic Changes Aligning with Classical Glucocorticoid Effects* , 2013, Molecular & Cellular Proteomics.

[9]  C. Watson,et al.  Estrogen- and xenoestrogen-induced ERK signaling in pituitary tumor cells involves estrogen receptor-α interactions with G protein-αi and caveolin I , 2012, Steroids.

[10]  T. Yamashita,et al.  Acute effects of glucocorticoids on ATP-induced Ca2+ mobilization and nitric oxide production in cochlear spiral ganglion neurons , 2005, Neuroscience.

[11]  Lei Liu,et al.  Rapid inhibitory effect of glucocorticoids on airway smooth muscle contractions in guinea pigs , 2006, Steroids.

[12]  J. Bousquet,et al.  Rapid anti-secretory effects of glucocorticoids in human airway epithelium , 2006, Steroids.

[13]  M. Streiff,et al.  Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. , 2002, Blood.

[14]  C. Jiang,et al.  Dexamethasone induces rapid promotion of norepinephrine‑mediated vascular smooth muscle cell contraction. , 2013, Molecular medicine reports.

[15]  L. Muglia,et al.  Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages , 2017, The Journal of Immunology.

[16]  X. Li,et al.  Rapid activation of ERK1/2 mitogen-activated protein kinase by corticosterone in PC12 cells. , 2001, Biochemical and biophysical research communications.

[17]  T. Berki,et al.  The regulation of the mitochondrial apoptotic pathway by glucocorticoid receptor in collaboration with Bcl-2 family proteins in developing T cells , 2016, Apoptosis.

[18]  B. Harvey,et al.  Rapid and non‐genomic reduction of intracellular [Ca2+] induced by aldosterone in human bronchial epithelium , 2001, The Journal of physiology.

[19]  S. Krauss,et al.  Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes. , 1997, The Biochemical journal.

[20]  J. Qiu,et al.  Corticosterone‐induced rapid phosphorylation of p38 and JNK mitogen‐activated protein kinases in PC12 cells , 2001, FEBS letters.

[21]  H. Mutsaers,et al.  Dexamethasone Enhances Oxidative Stress-Induced Cell Death in Murine Neural Stem Cells , 2012, Neurotoxicity Research.

[22]  Y. Tsuji,et al.  Quantification of caveolin isoforms using quantitative real-time RT-PCR, and analysis of promoter CpG methylation of caveolin-1alpha in human T cell leukemia cell lines. , 2006, International journal of molecular medicine.

[23]  S. Orrenius,et al.  Cyclic AMP potentiates glucocorticoid‐induced endogenous endonuclease activation in thymocytes 1 , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  T. Berki,et al.  Developmental shift in TcR-mediated rescue of thymocytes from glucocorticoid-induced apoptosis. , 2008, Immunobiology.

[25]  G. Haegeman,et al.  Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: Survival of the fittest regulator of the immune system? , 2010, Brain, Behavior, and Immunity.

[26]  Yi-Zhang Chen,et al.  Evoked intracellular Ca2+ elevations in HT4 neuroblastoma cells , 2002, Neuroreport.

[27]  X. Ni,et al.  Glucocorticoid acts on a putative G protein-coupled receptor to rapidly regulate the activity of NMDA receptors in hippocampal neurons. , 2012, American journal of physiology. Endocrinology and metabolism.

[28]  B. Harvey,et al.  Nongenomic effects of aldosterone on Ca2+ in M-1 cortical collecting duct cells. , 2000, Kidney international.

[29]  T. Berki,et al.  Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells. , 2010, Immunobiology.

[30]  C. Jiang,et al.  Rapid nongenomic effects of glucocorticoids on allergic asthma reaction in the guinea pig. , 2003, The Journal of endocrinology.

[31]  J. Bousquet,et al.  Rapid non‐genomic inhibition of ATP‐induced Cl− secretion by dexamethasone in human bronchial epithelium , 2002, The Journal of physiology.

[32]  J. Gardner,et al.  Glucocorticoid modulation of Ca2+ homeostasis in human B lymphoblasts , 1999, The Journal of physiology.

[33]  Yue Wang,et al.  Rapid non-genomic inhibitory effects of glucocorticoids on human neutrophil degranulation , 2004, Inflammation Research.

[34]  Ronit Vogt Sionov,et al.  Glucocorticoid-Induced Apoptosis: Revisited: A Novel Role for Glucocorticoid Receptor Translocation to the Mitochondria , 2006, Cell cycle.

[35]  R. Borski,et al.  Cortisol rapidly reduces prolactin release and cAMP and 45Ca2+ accumulation in the cichlid fish pituitary in vitro. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Yi-Zhang Chen,et al.  Inhibition of ATP-induced calcium influx in HT4 cells by glucocorticoids: involvement of protein kinase A , 2005, Acta Pharmacologica Sinica.

[37]  M. Flint,et al.  Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer , 2017, Breast Cancer Research.

[38]  Robert F Lemanske,et al.  6. Asthma☆☆☆ , 2003, Journal of Allergy and Clinical Immunology.

[39]  T. W. van der Mark,et al.  A guinea pig model of acute and chronic asthma using permanently instrumented and unrestrained animals , 2006, Nature Protocols.

[40]  Minggao Li,et al.  [Rapid inhibitory effect of glucocorticoids on peak of [Ca2+]i and PLC in airway smooth muscle]. , 2010, Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology.

[41]  J. Qiu,et al.  A rapid, nongenomic action of glucocorticoids in rat B103 neuroblastoma cells. , 2002, Biochimica et biophysica acta.

[42]  A. Halayko,et al.  Caveolae and caveolins in the respiratory system. , 2008, Current molecular medicine.

[43]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[44]  H. Gong,et al.  Dexamethasone rapidly inhibits glucose uptake via non-genomic mechanisms in contracting myotubes. , 2016, Archives of biochemistry and biophysics.

[45]  Taiki Takahashi,et al.  Corticosterone acutely prolonged N‐methyl‐d‐aspartate receptor‐mediated Ca2+ elevation in cultured rat hippocampal neurons , 2002, Journal of neurochemistry.

[46]  G. Burnstock,et al.  P2X receptor immunoreactivity in the rat cochlea, vestibular ganglion and cochlear nucleus , 1999, Hearing Research.

[47]  G. Chrousos,et al.  The Role of S-Palmitoylation of the Human Glucocorticoid Receptor (hGR) in Mediating the Nongenomic Glucocorticoid Actions. , 2017, Journal of molecular biochemistry.

[48]  Peter W. Swaan,et al.  Post‐translational modifications of transporters , 2018, Pharmacology & therapeutics.

[49]  D. Ray,et al.  Caveolin mediates rapid glucocorticoid effects and couples glucocorticoid action to the antiproliferative program. , 2008, Molecular endocrinology.

[50]  H. Meurs,et al.  Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. , 2003, Trends in pharmacological sciences.

[51]  J. Loscalzo.  Nitric oxide and vascular disease. , 1995, New England Journal of Medicine.

[52]  A. Psarra,et al.  Glucocorticoid receptors and other nuclear transcription factors in mitochondria and possible functions. , 2009, Biochimica et biophysica acta.

[53]  M. Wehling,et al.  Nongenomic effects of aldosterone on intracellular Ca2+ in vascular smooth muscle cells. , 1995, Circulation research.

[54]  D. Jain,et al.  Decreased sodium-potassium and calcium adenosine triphosphatase activity in asthma: modulation by inhaled and oral corticosteroids. , 1999, The Indian journal of chest diseases & allied sciences.

[55]  R. Locher,et al.  Stimulation of the phosphoinositide signalling system as a possible mechanism for glucocorticoid action in blood pressure control , 1988, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[56]  M. Moskowitz,et al.  Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase , 2002, Nature Medicine.

[57]  K. Leung,et al.  Protopanaxadiol and protopanaxatriol bind to glucocorticoid and oestrogen receptors in endothelial cells , 2009, British journal of pharmacology.

[58]  F. Buttgereit,et al.  Non-genomic glucocorticoid effects to provide the basis for new drug developments , 2006, Molecular and Cellular Endocrinology.

[59]  A. Scheffold,et al.  Membrane glucocorticoid receptors are down regulated by glucocorticoids in patients with systemic lupus erythematosus and use a caveolin-1-independent expression pathway , 2006, Annals of the rheumatic diseases.

[60]  A. Psarra,et al.  The mitochondrion as a primary site of action of steroid and thyroid hormones: Presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells , 2006, Molecular and Cellular Endocrinology.

[61]  Lei Li,et al.  Plasma membrane localization and function of the estrogen receptor α variant (ER46) in human endothelial cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Yan Liu,et al.  Glucocorticoid decreases airway tone via a nongenomic pathway , 2012, Respiratory Physiology & Neurobiology.

[63]  H. Nojima,et al.  Induction of the Cyclin-dependent Kinase Inhibitor p21Sdi1/Cip1/Waf1 by Nitric Oxide-generating Vasodilator in Vascular Smooth Muscle Cells* , 1997, The Journal of Biological Chemistry.

[64]  M. Moskowitz,et al.  Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. , 2002, The Journal of clinical investigation.