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An Investigation Into the in Vitro and in Vivo Function of Murine MRP-14 (S100A9)

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An Investigation Into the in Vitro and in Vivo Function of Murine MRP-14 (S100A9) An Investigation into the In Vitro and In Vivo Function of Murine MRP-14 (S100A9) Josie A. R. Hobbs March 2003 Supervisors Dr. Nancy Hogg (Cancer Research UK) Prof. Peter Beverley (University College London) This thesis is submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy at the University of London ProQuest Number: U643505 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643505 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract MRP-14 and its heterodimeric partner, MRP-8 are highly expressed in neutrophils and monocytes where they constitute 40% and 1% of the total cytosolic protein respectively. They are both low molecular weight proteins that belong to the SI GO family of Ca^^-binding proteins. Using the air pouch model of inflammation it has been demonstrated that recombinant murine MRP-14 (rMRP-14) is a potent chemoattractant for myeloid cells in vivo (May, 1999). While rMRP-14 did not directly cause chemotaxis or activation of myeloid cells in vitro, it caused a rapid elevation in the levels of cytokines in air pouch exudate, suggesting that rMRP-14 causes leukocyte influx via an indirect mechanism. As a control for endotoxin involvement, an air pouch experiment was performed using LPS insensitive mice. rMRP-14 did not produce an influx of cells. In addition, picogram levels of LPS, equivalent to the level of endotoxin contaminaton in rMRP-14, induced similar chemokines to rMRP14 in the air pouch. Therefore it is likely the effect of rMRP-14 in vivo is due to endotoxin contamination. Myeloid cells from MRP-14' ' mice were characterised. MRP-8 mRNA, but not protein, was present in these cells, suggesting that the stability of MRP-8 protein is dependent on MRP-14 expression. A compensatory increase in other proteins was not detected and myeloid cell development was unaffected in MRP-14' ' mice. MRP- 14'^' neutrophils had a reduced Ca^^ flux in response to suboptimal levels of MIP-2. The ability of MRP-14' ' cells to perform chemotaxis, apoptosis or superoxide burst was unaffected. In an in vivo model of pneumonia, MRP-14' ' mice were less able to contain the infection than MRP-14^^^ mice. It is proposed that MRP-14 may not be dispensible for all myeloid cell functions. The role of MRP-8 during embryonic development was also investigated. MRP-8 was expressed by cells of both maternal and fetal origin. MRP-14' ' mice expressed reduced levels of MRP-8 and developed normally. This is in contrast to MPR-8' ' mice that die in utero (Passey et al, 1999a). Therefore, MRP-8 appears to play an essential function during development that is independent of MRP-14. Acknowledgments I would like to thank Nancy my supervisor, for all her encouragement, guidance and relentless optimism. I am also very grateful to members of the MRP club, Eileen McNeill and Meg Mathies, for sharing my frustrations and understanding my MRP- 8''^' rants, and Rob for his sound mousey post doctoral advice and help with the big in vivo experiments. Also thanks to Ali McDowall, Cath Giles, Melanie Laschinger, Andrew Smith and Paula Stanley, for all their support and for making the MacLab such a friendly working environment. Past lab members that deserve a special mention are Mat “SI00 trivia” Robinson, Madelon Bracke, Birgit Leitinger, and Jonathan Edgeworth for our fun neutrophil collaborations. I would also like to thank Peter Beverley for all his guidance and support over the past 3 years. I am extremely grateful to all the staff in the Biological Resources unit at Cancer Research UK. Special thanks to Barbara and Mark who have cared for the MRP-14 ^ mice and taught me a lot about managing a mouse colony. Thanks to Gill, Carla and Clare for all their assistance in the mouse house. A lot of my work would have not been possible without the excellent help of members of the support labs at Cancer Research UK. Thank you to Derek, Gary, Cathy and Ayad from the FACSlab and Dave from the 2D gel lab. On a technical note, I thank George Elia and his lab for making literally 1000s of embryo sections and performing the immunohistochemistry presented in this thesis. I would also like to thank Rosemary Jeffery for the beautiful in situ hybridisations presented in this thesis and Richard Poulsom for his lessons in Photoshop and microscopy. I would like to thank Anna, Becky, Ceri, Christian, Neil, Robin, Ryan, Sarah, Toni and co. for many happy evenings in the George! Finally, thank you to Rich for removing all “I” from this thesis and for keeping me sane over three intensive months of write up! I! Table of contents Abstract..........................................................................................................................2 Acknowledgments......................................................................................................... 3 Table of contents............................................................................................................4 Table of figures............................................................................................................14 Abbreviations..............................................................................................................18 CHAPTER 1................................................................................................................21 Introduction.................................................................................................................21 1.1 The innate immune system.................................................................................21 1.1.1 The response to infection ............................................................................21 1.1.2 Leukocyte recruitment .................................................................................23 Rolling ...............................................................................................................23 Activation ......................................................................................................... 26 Firm adhesion ...................................................................................................27 Diapedesis ........................................................................................................ 29 Migration through the basement membrane and tissues .................................30 1.1.3 The role of neutrophils in host defense ...................................................... 30 1.2 Ca^^ signalling and Ca^^ binding proteins ..........................................................33 1.2.1 Ca^^ as a secondary messenger ................................................................... 33 1.2.2 Ca^^ influx pathways................................................................................... 35 1.2.3 Ca^^ storage organelles ................................................................................37 1.3 The SI00 protein family.................................................................................... 39 1.3.1 S100 introduction .......................................................................................39 4 Table of contents 1.3.2 S100 protein structure .................................................................................42 1.3.3 induced conformationl change ............................................................42 1.3.4 Ca^^ binding affinities of S100 proteins in vivo ..........................................45 1.3.5 Zn^^ and Cu^^binding .................................................................................45 1.3.6 Target binding by SlOO proteins .................................................................46 1.3.7 Gene structure and genome localisation ..................................................... 47 1.3.8 Expression of SlOO proteins ....................................................................... 49 1.3.9 8100 expression in disease ......................................................................... 49 1.3.10 General functions of SlOO proteins ...........................................................50 Intracellular functions of SlOO proteins ...........................................................51 Extracellular functions of SlOO proteins ......................................................... 51 1.3.11 Receptors ...................................................................................................52 1.3.12 Insights into SlOO function from mouse models ..................................... 53 1.4 The MRP proteins............................................................................................ 54 1.4.1 MRP introduction ........................................................................................ 54 1.4.2 Protein structure ...........................................................................................55 1.4.3 Structure of MRP-8 ..................................................................................... 57 1.4.4 Structure of MRP-14 ...................................................................................58
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