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P2X7 Receptor-Induced CD23 Shedding from B Cells Aleta Pupovac University of Wollongong, [email protected]

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P2X7 Receptor-Induced CD23 Shedding from B Cells Aleta Pupovac University of Wollongong, Ap251@Uow.Edu.Au University of Wollongong Research Online University of Wollongong Thesis Collection University of Wollongong Thesis Collections 2014 P2X7 receptor-induced CD23 shedding from B cells Aleta Pupovac University of Wollongong, [email protected] Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] P2X7 receptor-induced CD23 shedding from B cells A thesis submitted in fulfilment of the requirements for the award of the degree Doctor of Philosophy from UNIVERSITY OF WOLLONGONG by Aleta Pupovac Bachelor of Biotechnology (Adv) (Hons) Illawarra Health and Medical Research Institute School of Biological Sciences 2014 THESIS CERTIFICATION I, Aleta Pupovac, declare that this thesis, submitted in fulfilment of the requirements for the award of Doctor of Philosophy, in the Department of Biological Sciences, University of Wollongong, is wholly my own work unless otherwise referenced or acknowledged. The document has not been submitted for qualifications at any other academic institution. Aleta Pupovac 2014 i ACKNOWLEDGEMENTS I would like to thank my supervisor, Ron Sluyter, for providing me with the skills and patience to tackle science confidently in the future. Your knowledge, guidance and support were essential in the completion of this project, and have moulded me into the scientist that I always hoped to be. I will be forever grateful that you gave me the opportunity to be a part of your lab, and for your excellent supervision. A student cannot ask for a better supervisor. Also thanks to my co-supervisor Marie Ranson, for providing helpful advice over the years. To all the past and current members of the Sluyter lab, I enjoyed working with all of you. In particular, Pan, Safina, Mar and Rach, I thank you for your support and entertainment on most days in and out of the lab, but more so during the challenging times thrown at me by science over the years. Also a big thankyou to Vanessa Sluyter for providing assistance and order in the lab, your level of organisation is something I hope to achieve one day. I also want to thank people from neighbouring labs (past and present), including Simon, Blake, James, Carola, Bec, Corky, Di, Raf and Dave for laughs, inspiration, scientific/life advice and support. Meeting all of you was an unexpected (even delightful) highlight of my PhD experience. Finally, I want to thank my family and friends, including those mentioned already and those outside of research, for your love and support. Without you I wouldn’t have had the motivation or strength to achieve what I have and no words can express my gratitude to you. ii TABLE OF CONTENTS THESIS CERTIFICATION ........................................................................................... I ACKNOWLEDGEMENTS ........................................................................................... II LIST OF FIGURES .................................................................................................. VIII LIST OF TABLES ...................................................................................................... XII LIST OF ABBREVIATIONS .................................................................................. XIII CHAPTER PUBLICATIONS ................................................................................. XVII LIST OF CONFERENCE PRESENTATIONS ..................................................... XIX ABSTRACT ................................................................................................................. XX CHAPTER 1: INTRODUCTION .................................................................................. 1 1.1 CD23 ......................................................................................................................................................... 2 1.1.1 Structure and features ........................................................................................................................ 2 1.1.2 Distribution ........................................................................................................................................ 3 1.1.3 Roles of membrane CD23 ................................................................................................................. 4 1.1.4 Generation and roles of soluble CD23 .............................................................................................. 5 1.1.4.1 Shedding of membrane CD23 .................................................................................................... 5 1.1.4.2 Roles of soluble CD23 and IgE ................................................................................................. 7 1.1.4.3 Roles of soluble CD23 as a cytokine ......................................................................................... 7 1.1.5 Soluble CD23 in disease .................................................................................................................... 9 1.2 CXCL16 .................................................................................................................................................. 10 1.2.1 Structure and features ...................................................................................................................... 10 1.2.2 Distribution of CXCL16 .................................................................................................................. 12 1.2.3 Roles of membrane CXCL16 .......................................................................................................... 13 1.2.4 Generation and roles of soluble CXCL16 ....................................................................................... 13 1.2.4.1 Shedding of membrane CXCL16 ............................................................................................ 13 1.2.4.2 Roles of soluble CXCL16 ........................................................................................................ 14 1.2.5 Soluble CXCL16 and disease .......................................................................................................... 15 1.3 Purinergic signalling and purinergic receptors ................................................................................. 16 1.3.1 Introduction ...................................................................................................................................... 16 1.3.2 P2Y receptors ................................................................................................................................... 17 1.3.3 P2X receptors ................................................................................................................................... 18 1.4 The P2X7 receptor ................................................................................................................................ 19 1.4.1 Structure and function ..................................................................................................................... 19 1.4.2 Polymorphic and splice variants ...................................................................................................... 21 iii 1.4.2.1 Single nucleotide polymorphisms ............................................................................................ 21 1.4.2.2 Splice variants .......................................................................................................................... 23 1.4.3 Pharmacology .................................................................................................................................. 24 1.4.4 Distribution ...................................................................................................................................... 27 1.4.5 Downstream events .......................................................................................................................... 27 1.4.5.1 IL-1 cytokine family member secretion .................................................................................. 28 1.4.5.2 Cell death and proliferation ..................................................................................................... 28 1.4.5.3 Transcription factor activation ................................................................................................. 29 1.4.5.4 ROS formation ......................................................................................................................... 29 1.4.5.5 Membrane-related events ......................................................................................................... 30 1.4.6 Disease ............................................................................................................................................. 30 1.5 Nucleotide-induced shedding of cell surface molecules .................................................................... 32 1.5.1 Introduction ...................................................................................................................................... 32 1.5.2 CD23 ................................................................................................................................................ 35 1.5.3 CD62L .............................................................................................................................................. 37 1.5.4 CD21 ...............................................................................................................................................
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