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(2) On the cover: Murine neutrophils from the bronchoalveolar space stained with the antineutrophil antibody NIMP-R14 and Liquid Permanent Red. Photo by Elin Silverpil.. © Elin Silverpil 2010 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without written permission.. ISBN 978-91-628-8109-2. Printed by Geson Hylte Tryck, Göteborg, Sweden 2010.

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(11) TABLE OF CONTENTS ABBREVIATIONS!............................................................................................................................!11 INTRODUCTION!..............................................................................................................................!13 Innate immunity ................................................................................................................... 13 Pathogen-associated molecular patterns and their receptors ............................................ 13 Neutrophils ....................................................................................................................... 14 Macrophages .................................................................................................................... 15 Acute inflammation .............................................................................................................. 16 Necrosis ............................................................................................................................ 17 IL-17 ..................................................................................................................................... 18 Cellular sources of IL-17.................................................................................................. 18 IL-17-producing cells other than T cells .......................................................................... 24 IL-17 family members ...................................................................................................... 24 Downstream actions of IL-17 ........................................................................................... 25 Resolution of inflammation .................................................................................................. 28 Clearance of inflammatory cells ...................................................................................... 29 Chronic inflammatory diseases ............................................................................................ 30 Anti-inflammatory pharmacology ........................................................................................ 31 Dexamethasone and cyclosporine A ................................................................................ 31 Paradigms of IL-17 over the years ....................................................................................... 32 AIMS!....................................................................................................................................................!33 General aims ......................................................................................................................... 33 Specific aims ........................................................................................................................ 33 METHODS!.........................................................................................................................................!34 In vivo experiments .............................................................................................................. 34 Mice .................................................................................................................................. 34 In vitro experiments ............................................................................................................. 36 Bronchoalveolar lavage in humans .................................................................................. 36 Isolation of cells ............................................................................................................... 37 Stimulation of cells........................................................................................................... 38 Neutrophil apoptosis assay ................................................................................................... 40 Assessment of phagocytosis ................................................................................................. 41 Enzyme-linked immunosorbent assay .................................................................................. 42 mRNA measurements .......................................................................................................... 42 Flow cytometry .................................................................................................................... 42 Statistical analysis ................................................................................................................ 43 Paper I .............................................................................................................................. 43 Paper II ............................................................................................................................. 43 Paper III ............................................................................................................................ 44 RESULTS!............................................................................................................................................!45 Paper I .................................................................................................................................. 45 LPS treatment increases IL-17 release and neutrophil numbers in the murine bronchoalveolar space ...................................................................................................... 45 Pharmacotherapy decreases IL-17 release and BAL cell numbers in the bronchoalveolar space ................................................................................................................................. 46 Pharmacotherapy decreases numbers of CD3+ IL-17+ cells in lung tissues and in the bronchoalveolar space ...................................................................................................... 46 High proportion of CD3-IL-17+ cells in lung tissues and in the bronchoalveolar space. 47.

(12) Pharmacotherapy decreases IL-17 mRNA expression in lung tissues and reduces IL-17 release in vitro .................................................................................................................. 48 Paper II ................................................................................................................................. 49 IL-17 enhances neutrophil apoptosis and MPO release ................................................... 49 IL-17 increases the phagocytosis of murine neutrophils and latex beads ........................ 50 IL-17 stimulates the release of sLOX-1 but not MIP-2 ................................................... 50 Paper III ................................................................................................................................ 50 Following S. aureus infection, IL-17-knockout mice release more IL-23 than wild-type mice .................................................................................................................................. 50 Following LPS stimulation, anti-IL-17 antibody-treated mice release more IL-23 than isotype control-treated mice ............................................................................................. 51 IL-17 treatment decreases IL-23 in mice ......................................................................... 51 IL-17 treatment decreases IL-23 release from human cells of the monocytic lineage in vitro .................................................................................................................................. 52 DISCUSSION!......................................................................................................................................!53 Paper I .................................................................................................................................. 53 IL-17-containing cells ...................................................................................................... 53 Anti-inflammatory drugs .................................................................................................. 55 Paper II ................................................................................................................................. 57 Apoptosis .......................................................................................................................... 57 Myeloperoxidase .............................................................................................................. 58 MIP-2 and soluble LOX-1................................................................................................ 58 Phagocytosis ..................................................................................................................... 59 Paper III ................................................................................................................................ 60 Negative regulation downstream of IL-17RA .................................................................. 60 IL-17 dose dependency .................................................................................................... 61 What happens when IL-17 decreases IL-23? ................................................................... 61 GENERAL!DISCUSSION!..................................................................................................................!62 Effect of IL-17 on macrophage phenotype .......................................................................... 62 Dose dependency.................................................................................................................. 62 Why IL-17 is considered to be a pro-inflammatory cytokine .............................................. 64 The usual suspect ................................................................................................................. 65 Do not mistake IL-17 for Th17 ........................................................................................ 65 SUMMARY!.........................................................................................................................................!66 CONCLUSIONS!..................................................................................................................................!67 General conclusion ............................................................................................................... 67 Specific conclusions ............................................................................................................. 67 Paper I .............................................................................................................................. 67 Paper II ............................................................................................................................. 68 Paper III ............................................................................................................................ 68 POPULÄRVETENSKAPLIG!SAMMANFATTNING!...................................................................!69 Modulerande roll för IL-17 vid inflammation i luftvägarna ................................................ 69 Delarbete I ........................................................................................................................ 69 Delarbete II ....................................................................................................................... 70 Delarbete III ..................................................................................................................... 70 ACKNOWLEDGEMENTS!................................................................................................................!72.

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