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The Anti-Inflammatory Role of Nuclear Receptors in Dendritic Cells

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The Anti-Inflammatory Role of Nuclear Receptors in Dendritic Cells The Anti-Inflammatory Role of Nuclear Receptors in Dendritic Cells A thesis submitted for the degree of Ph.D. By Mary Canavan B.Sc. (Hons), March 2012. Based on research carried out at School of Biotechnology, Dublin City University, Dublin 9, Ireland. Under the supervision of Dr. Christine Loscher. Declaration I hereby certify that this material, which I now submit for assessment on the programme of study leading to the award of Doctor of Philosophy is entirely my own work, that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge breach any law of copyright, and has not been taken from the work of others and to the extent that such work has been cited and acknowledged within the text of my work. Signed: ____________________ ID No.:__54351789__ Date: ______________ ACKNOWLEDGEMENTS There are so many people that I would like to thank and definitely not enough space to say exactly how grateful I am to you all. I have been lucky enough to work with an amazing group of people over the past few years. Firstly I would like to thank Christine for all your help, support, enthusiasm and patience – and for telling me not to do anymore of those p50 blots! I have thoroughly enjoyed working with you and learning from you over the last few years. To everyone in the Lab – you are the reason why I have such great memories when I look back at my time in DCU. Whenever I think of failed experiments, tough days and tears, there is always a great memory of you guys that goes along with it. Laura – there would have been a lot more tears and lot less laughs without you. I seriously considered adding the term “righting the world” to my Materials and Methods section! Ciara –thank you so much for all your help as I was finishing up. You were starting a new job and still always had time for my endless questions. Joey – thanks for giving me my most hardcore “memory” – 24hr drinking session!!!. I'm looking forward to celebrating with you soon Dr deCourcey. Fiona (and the little man ) the lab would definitely be a lot less cheerful without you in it. I don’t know how you do it, but you always have time for everyone else and always have a smile to go with it ! To Croatia’s most valuable export – Maja, you and Francis have been such great friends to me. Thank you for always listening. You always told me things I needed to hear and not always the things I wanted to hear at the time – the sign of a true friend. To Mark, thank you for your unwavering enthusiasm. It really is infectious (although I can’t believe you haven’t been broken yet!!). To Kathy and Iza – the newbies you are a breath of fresh air in the lab and I am slightly jealous of the the memories and experiences you have ahead of you. To Paul, Joey, Gillian and Carolyn – thank you for all your help with the animal studies – without which I could not have I done this research. Thank you to everyone in the BRS – all the trips and nights out are what kept me sane over the last few years. To my family, I owe you the biggest thank you of all. Thank you for all your love, support and patience. Thank you for understanding and for always being there when I needed you. I know how lucky I am that even after missed birthdays, missed phonecalls and missed visits you were still always on my side supporting me. Finally a very special thank you to Ze and Reja – for never letting me forget whats really important. xxx II PUBLICATIONS Canavan M, McCarthy C, Ben Larbi N, Dowling J, Kagechika H, Moynagh P, Melgar S, Loscher CE (2012) Liver X Receptor suppresses the production of the IL-12 family of cytokines via NFκBp50 Submitted to the Journal of Immunology Dowling J., McCoy C., Doyle S., BenLarbi N., Canavan M .,O'Neill L., Loscher CE (2012) Conjugated linoleic acid suppresses IRF3 activation via modulation of CD14 J Nutr Biochem. 2012 Aug 15. [Epub ahead of print] Draper E., Reynolds C. M., Canavan M., Mills K. H., Loscher C., Roche H. M. (2011) Omega-3 fatty acids attenuate dendritic cell function via NFκB independent of PPARy. Journal of Nutritional Biochemistry 2011 Aug;22 (8):784-90 Canavan M., deCourcey J., Ben Larbi N., Loscher CE. LXR suppresses IL-17 secretion from Th17 cells through an interaction with RXR. (Manuscript in preparation for submission to the Journal of Immunology and Cell Biology) McCarthy C, Murphy C, Canavan M, Dowling JK, Guiry PJ, Loscher CE. A purified marine compound isolated from the marine sponge Membranipora membranacea suppresses macrophage function following exposure to bacterial but not viral ligands. (Manuscript in preparation) III ABSTRACT The liver X receptor (LXR), peroxisome proliferator activated receptor γ (PPARγ) and retinoid X receptor (RXR) are members of the nuclear receptor superfamily. Once activated these receptors can form heterodimers with each other in order to control key processes within the cell. The role of these NRs in immune cells is relatively uncharacterized; therefore we examined the effects of their activation on cytokine production and cell surface marker expression on murine bone marrow-derived dendritic cells (BMDC). We demonstrated that these NR agonists can specifically modulate the IL-12 family of cytokines as well as altering the expression of co- stimulatory markers on the cell surface. We also show that the effect of LXR activation on these IL-12 family of cytokines is a result of heterodimerising with RXR. Furthermore, we found that expression of LXR was regulated during inflammatory disease. In order to determine the mechanism by which LXR exerts its anti- inflammatory effects we next examined its effects on DCs activated by a panel of TLR ligands. These results showed that the target of LXR was a common element of the TLR pathways; therefore we determined its effects on NFκB and IRF3 activation. Interestingly, we show that LXR: RXR heterodimers are important in NFκB inhibition but not IRF3. We next showed that LXR can specifically target the p35, p40 and EBI3 subunits of the IL-12 cytokine family. Given that these subunits are directly under the control of the NFκB subunit p50, we examined the effect of LXR activation on this p50 subunit and showed that LXR colocalises in DC with p50 and that LXR activation prevents translocation of the p50 subunit into the nucleus. In summary our study provides evidence for an anti-inflammatory role for LXR in DCs and highlights its potential as a therapeutic target for chronic inflammatory diseases. IV ABBREVIATIONS 9cRA 9 cis Retinoic acid ABCA1 ATP-binding cassette transporter 1 APC Antigen presenting cell APR Acute phase response AR Androgen receptor BAFF B cell activating factor BMDC Bone marrow derived dendritic cell CBP CREB binding protein CD Crohns disease CIA Collagen induced arthritis CNS Central nervous system CREB cAMP response element-binding CTLA-4 Cytotoxic T lymphocyte-associated antigen-4 CVD Cardiovascular disease DBD DNA binding domain DC Dendritic cell DLN Draining lymph node DSS Dextran sodium sulfate EAE Experimental autoimmune encephalomyelitis EBI3 Epstein Barr induced virus 3 ER Endoplasmic reticulum FXR Farnesoid X receptor GRR Glycine rich region IBD Inflammatory bowel disease IFN Interferon V IKK IκB kinase iNKT Invariant natural killer T cell IRAK Interleukin-1 receptor–associated kinase IRF3 Interferon regulatory factor 3 KO Knock out LBD Ligand binding domain LBP LPS binding protein LPS Lipopolysaccharide LXR Liver X receptor MAPK Mitogen-activated protein kinase MDDC Monocyte derived dendritic cell MHC Major histocompatibility complex MS Multiple sclerosis MyD88 Myeloid differentiation factor 88 NK Natural Killer Nor-1 Neuron-derived orphan receptor 1 Nurr1 Nuclear receptor related 1 protein Nurr77 Nerve growth factor-induced clone B OPC Oligodendrocyte progenitor cell PAMP Pathogen associated molecular pattern Poly:IC Polyinosinic:polycytidylic acid PPAR Peroxisome proliferator activated receptor PRR Pattern recognition receptor PXR Pregnane X receptor RA Rheumatoid arthritis RHD Rel homology domain RHIM Rip homotypic interaction motif VI RIP Ribosome inactivating protein RXR Retinoid X receptor SUMO Small ubiquitin related modifier TAK Transforming growth factor-beta-activated kinase TCR T cell receptor Th T helper TIR Toll/Interleukin-1 receptor domain TLR Toll-like receptor TR Thyroid receptor TRAF TNF receptor-associated factors TRAM TRIF related adaptor molecule TRIF TIR-domain-containing adapter-inducing interferon-β TZD Thiazolidinedione UC Ulcerative colitis VDR Vitamin D receptor VSV Vesicular stomatitis virus VII TABLE OF CONTENTS ACKNOWLEDGEMENTS.........................................................................................................................I PUBLICATIONS......................................................................................................................................III ABSTRACT...............................................................................................................................................IV ABBREVIATIONS....................................................................................................................................V TABLE OF CONTENTS.......................................................................................................................VIII CHAPTER 1 .................................................................................................................... 1 1.0 INNATE IMMUNITY: AN OVERVIEW ............................................................................ 2 1.1 OVERVIEW
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