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Modulation of Glucocorticoid-Inducible Gene Expression: Effects of Inflammatory Stimuli and Long-Acting Β2-Adrenoceptor Agonists

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Modulation of Glucocorticoid-Inducible Gene Expression: Effects of Inflammatory Stimuli and Long-Acting Β2-Adrenoceptor Agonists University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2014-09-15 Modulation of glucocorticoid-inducible gene expression: Effects of inflammatory stimuli and long-acting β2-adrenoceptor agonists Rider, Christopher Francis Rider, C. F. (2014). Modulation of glucocorticoid-inducible gene expression: Effects of inflammatory stimuli and long-acting β2-adrenoceptor agonists (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/26976 http://hdl.handle.net/11023/1764 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Modulation of glucocorticoid-inducible gene expression: Effects of inflammatory stimuli and long-acting β2-adrenoceptor agonists by Christopher Francis Rider A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN CARDIOVASCULAR AND RESPIRATORY SCIENCES CALGARY, ALBERTA SEPTEMBER, 2014 © Christopher Francis Rider 2014 Abstract Glucocorticoids, acting on the glucocorticoid receptor (GR; NR3C1), are the most effective medication for controlling inflammation in the majority of asthmatics. However, some asthmatics, particularly those with severe disease, have reduced responses to glucocorticoids, a condition known as glucocorticoid resistance. Likewise, glucocorticoids have reduced effectiveness in asthmatics who smoke and during exacerbations, which are frequently induced by human rhinovirus (HRV) infection. Glucocorticoids reduce inflammatory protein production by directly inhibiting inflammatory transcription factors, including nuclear factor-kappa B (NF- κB) and by enhancing the expression of potentially anti-inflammatory genes (transactivation). The importance of transactivation in glucocorticoid activity is increasingly apparent, but the impact of inflammatory mediators on anti-inflammatory gene expression is understudied. Human bronchial epithelial, BEAS-2B, cells stably transfected with a 2×glucocorticoid response element (GRE) reporter system, which models glucocorticoid-inducible gene expression, demonstrate concentration-dependent activation by glucocorticoids. However, dexamethasone-induced 2×GRE activation was time-dependently reduced by pre-treatment with inflammatory mediators, including tumor necrosis factor (TNF), interleukin-1β (IL1B) and cigarette smoke extract (CSE). Furthermore, TNF pre-treatment decreased dexamethasone-induced mRNA expression of genes with potentially anti-inflammatory activity, including cyclin dependent kinase inhibitor 1C (CDKN1C) and TSC22 domain family protein 3 (TSC22D3/GILZ), in bronchial epithelial and airway smooth muscle cells. Likewise, pre-incubations with HRV or the synthetic double- stranded viral RNA mimetic polyinosinic:polycytidylic acid (poly(I:C)) reduced dexamethasone- induced 2×GRE activation. Poly(I:C) also reduced dexamethasone-induced CDKN1C ii expression. Approaches to reverse TNF-induced glucocorticoid hyporesponsiveness were evaluated, including addition of long-acting β2-adrenoceptor agonists (LABAs), use of novel GR agonists and inflammatory signalling pathway inhibition. LABAs, such as formoterol, potentiated 2×GRE reporter activation and CDKN1C expression through a time- and PKA- dependent mechanism that did not enhance GR expression, agonist affinity or translocation, but instead allows for gene specific control. Therefore, LABA addition functionally reversed glucocorticoid hyporesponsiveness induced by TNF or poly(I:C). However, novel GR agonist- induced 2×GRE activation was repressed by TNF or poly(I:C) treatment, with the degree of repression correlating with agonist efficacy. Finally, inhibition of the NF-κB and c-Jun N- terminal kinase (JNK) mitogen activated protein kinase pathways partially reversed TNF- induced glucocorticoid hyporesponsiveness. These results may contribute to the development of improved treatments for combating glucocorticoid hyporesponsiveness during exacerbations and in severe asthma. iii Preface Genes and proteins in this thesis are referred to using their standardised names according to the HUGO Gene Nomenclature Committee (HGNC) as specified at http://genenames.org. Where possible, commonly used gene name acronyms are included in parentheses. One exception is the glucocorticoid receptor, which is referred to as GR, rather than NR3C1, throughout. Some experiments in chapters 3, 5 and 6 were conducted by Neil S. Holden, Joanna E. Chivers, Suharsh Shah, David Gaunt, Dong Yan or Robert Newton. This is specifically noted in individual figure legends. Many of the figures presented in this thesis have been published in the following manuscripts: Rider, C.F., King, E.M., Holden, N.S., Giembycz, M.A., and Newton, R. (2011). Inflammatory stimuli inhibit glucocorticoid-dependent transactivation in human pulmonary epithelial cells: rescue by long-acting beta2-adrenoceptor agonists. J. Pharmacol. Exp. Ther. 338, 860–869. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics. Reprinted with permission of the American Society for Pharmacology and Experimental Therapeutics. All rights reserved. Rider, C.F., Shah, S., Miller-Larsson, A., Giembycz, M.A., and Newton, R. (2013). Modulation of transcriptional responses by poly(I:C) and human rhinovirus: Effect of long-acting β2- adrenoceptor agonists. European Journal of Pharmacology 708, 60–67. Copyright © Elsevier B.V. Reprinted with permission from Elsevier. All rights reserved. Rider, C.F., Miller-Larsson, A., Proud, D., Giembycz, M.A., and Newton, R. (Submitted). Cytokine-induced loss of glucocorticoid function: Effect of kinase inhibitors, long-acting β2- adrenoceptor agonists and glucocorticoid receptor ligands. PloS ONE. Potential conflicts of interest: During my undergraduate degree I was an employee of AstraZeneca for one year. My initial PhD studentship was funded by a grant to RN from GlaxoSmithKline. Work on these projects and in the laboratories of Dr. Robert Newton and Dr. Mark Giembycz was funded by AstraZeneca, Gilead Sciences and GlaxoSmithKline. iv Acknowledgements I would like to thank my supervisor Rob Newton for his advice, guidance, skiing trips and stimulating conversation throughout my time as a student (both at Warwick and Calgary). I am yet to meet a supervisor with more energy, passion and enthusiasm for his work and there is no way I will ever be able to repay him for all the help he has given me. My co-supervisor Mark Giembycz has always been a calm and wise source of advice and I cannot thank him enough for his guidance throughout my studies in Calgary. Likewise, I am incredibly lucky that Quentin Pittman and Richard Leigh agreed to be my committee members; both have provided exceptional guidance, constructive feedback and have always gone the extra mile to support me throughout these studies (including retrieving tissue samples from my lungs for a microarray study). Thank you to all members of the Newton and Giembycz labs, past and present for all your help, advice and for making the lab a generally fun place to be. Thank you also to everyone in the Amrein, Kelly, Leigh, Proud and Slater labs. I would particularly like to acknowledge Wei Gong, Neil Holden, Manny Kaur and Sylvia Hills for everything they taught me, Suharsh Shah, David Gaunt and Dong Yan for data and Liz King (and Peter) for all of the above, plus help, consolation and guidance throughout my time in Calgary. I would like to thank the organisations that provided funding for my research: Alberta Innovates-Health Solutions (AI-HS), AstraZeneca, Canadian Institutes of Health Research (CIHR), GlaxoSmithKline (GSK), The Lung Association (Alberta & NWT) and the University of Calgary. For help and advice with experiments I would like to thank Magda Hudy, Claire Tacon, Suzanne Traves, Raza Zaheer, Pina Colarusso, Tehmeena Malik and Xiuling Wang. Thank you also to all the people who ensure you can get things done at the University, but are too rarely acknowledged, including the admin staff, cleaners, distribution services, waste disposal and maintenance. I would also like to thank all my teachers who encouraged me to study science, I could never have tackled a PhD without the base of knowledge you provided. A variety of people provided help and friendship throughout my other major endeavours, in the GSA, CRSA and CFD. Special thanks to Stefan, Lindsay, Melanie, Dave, Chris, Paul, Andrea, Jason, Brooke, Anna, Leslie, Keir, Lauren, Donald and Frans - you are all awesome! Last, but definitely not least, I would like to thank my friends and family in England (and elsewhere)! I appreciate you not disowning me (despite threats to the contrary) for deciding to pack up and move ~6940 km away and for all your support and visits from across 'the pond'. v Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ..............................................................................................................v List of Tables .......................................................................................................................x
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