Investigation of interleukin 1b synthesis and secretion by dendritic cells interplay between toll like receptor and FCG receptor

INVESTIGATION OF INTERLEUKIN 1B SYNTHESIS AND SECRETION BY DENDRITIC CELLS: INTERPLAY BETWEEN TOLL-LIKE RECEPTOR AND FCG RECEPTOR WU XIAOWEI NATIONAL UNIVERSITY OF SINGAPORE 2006 INVESTIGATION OF INTERLEUKIN 1B SYNTHESIS AND SECRETION BY DENDRITIC CELLS: INTERPLAY BETWEEN TOLL-LIKE RECEPTOR AND FCG RECEPTOR WU XIAOWEI (B Sc) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF MICROBIOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2006 ACKNOWLEDGEMENTS First of all, I would like to sincerely thank my supervisor, Associate Professor Lu Jinhua, for giving me the opportunity to pursue Master of Science in his laboratory and for his advice and encouragement throughout my study I am also grateful to Linda Wang, Jason Goh and Cao Weiping for their continued support during the course of my study My gratitude also extends to my laboratory colleagues and staffs from Professor Chua Kaw Yan’s lab, Professor Poh Chit Laa’s lab and National University Hospital Blood Donation Center for their generous help in this research project I would like to thank National University of Singapore for awarding me a research scholarship Last, but not least, my deepest love and appreciation to my parents I TABLE OF CONTENTS Acknowledgements I Table of contents II Summary VII List of tables VIII List of figures IX Manuscript in preparation XI Abbreviations XII Chapter Introduction 1.1 Overview of the immune system 1.2 Mononuclear phagocytes 1.2.1 Monocytes 1.2.2 Dendritic cells 1.2.2.1 Heterogeneity of dendritic cell subsets 1.2.2.2 DC maturation and migration 1.2.2.3 Antigen uptake, processing and presentation by DCs 11 1.2.2.4 Immune regulation by DCs 13 1.2.2.5 In vitro human DC differentiation models 15 1.3 Pattern recognition receptors 17 1.3.1 TLRs 18 1.3.1.1 TLR ligands 20 II 1.3.1.2 Expression of TLRs by cells of mononuclear phagocytes 22 1.3.1.3 Signal Transduction via TLRs 22 1.3.1.3.1 MyD88-dependent pathway 23 1.3.1.3.2 MyD88-independent pathway 24 1.3.1.4 Modulation of immune response by TLRs 26 1.4 Phagocytic receptors 28 1.4.1 FcγRs 30 1.4.1.1 Signal transduction via FcγRs 35 1.4.1.2 Genetic coding, structure and cell distribution of human FcγRs 39 1.4.1.3 Functions of FcγRs 42 1.5 Pro-inflammatory cytokines 46 1.5.1 IL-1 46 1.5.1.1 Functional properties of IL-1 47 1.5.1.2 Two forms of IL-1 48 1.5.2 IL-1β 49 1.5.2.1 Transcriptional regulation of IL-1β 50 1.5.2.2 Translational regulation of IL-1β 52 1.5.2.3 Post-translational cleavage of IL-1β 53 1.5.2.4 Secretion of IL-1β 54 1.6 Aims of the study 56 Chapter Materials and Methods III 2.1 Molecular Biology 58 2.1.1 Materials 58 2.1.1.1 DNA primer synthesis 58 2.1.2 Methods 58 2.1.2.1 Manipulation of RNA 58 2.1.2.1.1 Isolation of total RNA from cell culture 58 2.1.2.1.2 Quantitation of RNA 59 2.1.2.1.3 Reverse transcription 59 2.1.2.2 PCR 60 2.1.2.3 Electrophoresis of nucleic acids 61 2.1.2.4 Real-time PCR 61 2.2 Cell Biology 63 2.2.1 Materials 63 2.2.1.1 Stimuli 63 2.2.1.2 Antibodies 63 2.2.1.3 Pharmacological inhibitors 65 2.2.2 Methods 65 2.2.2.1 Isolation of human peripheral blood monocytes 65 2.2.2.2 Generation of macrophages and DCs from monocytes 66 2.2.2.3 Cell activation 67 2.2.2.4 Flow cytometry 67 IV 2.2.2.5 Enzyme-linked immunosorbent assay (ELISA) 68 2.2.2.6 Caspase-1 activity assay 69 2.2.2.7 Lactate dehydrogenase (LDH) assay 70 2.3 Protein chemistry 71 2.3.1 Protein concentration determination 71 2.3.2 SDS-polyacrylamide gel electrophoresis (SDS-PAGE) 72 2.3.3 Western blotting 72 2.4 Statistic analysis 73 Chapter Results 3.1 moDCs acquire distinct phenotypic properties after differentiation from monocytes 74 3.2 TLR activation elicits IL-1β secretion by monocytes but not moDCs 76 3.3 IL-4 confers on moDCs stringent control over IL-1β secretion 3.4 LPS induces IL-1β synthesis, processing but not secretion in moDCs 80 3.5 LPS/ imIgG co-stimulation induces IL-1β secretion from moDCs 3.6 ImIgG enhances LPS-induced IL-1β transcription, translation but down-regulates caspase-1 activity in moDCs 86 3.7 ImIgG stimulates IL-1β secretion from moDCs through FcγRII 91 3.8 Effect of signaling inhibitors on IL-1β secretion from moDCs 94 3.9 LPS/ imIgG-induced IL-1β secretion from moDCs involves Ca2+ influx 97 3.10 LPS/ imIgG-induced IL-1β secretion from moDCs requires the activation of P2X7R 100 78 82 V 3.11 Summary 105 Chapter Discusstion 4.1 The regulation of IL-1β production differs between monocytes and moDCs 106 4.2 FcγRs regulates IL-1β production by moDCs 109 4.3 FcγR crosslinking triggers P2X7R-mediated Ca2+ influx 113 4.4 Investigation of signal molecules involved in the regulation of IL-1β production 115 4.5 FcγRs, IL-1 and autoimmune disease 118 Appendix 122 References 124 VI SUMMARY Interleukin-1 (IL-1β) is a prototypic multifunctional cytokine It not only mediates host inflammatory response in innate immunity, but also modulates antigen-specific immunity It is implicated in the pathogenesis of autoimmune disease, such as rheumatoid arthritis 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(MR), scavenger receptor (SR) and complement receptor (CR); and (ii) those that sense pathogens and lead to the activation of pro-inflammatory pathways, e.g Toll- like receptors (TLRs) The principle functions of PRRs include: opsonization, activation of complement and coagulation cascades, phagocytosis, activation of 17 ... class-switching of T cell activated B cells While IL-10 and TGF-β can induce secretion of IgA1, expression of IgA2 appears to be strictly dependent on a direct interaction between B cells and DCs (Fayette et al., 1997) (iv) NK and NKT cell activation Recent data have established an important role for DCs in innate immune responses by NK and NK T cells (Rossi and Young, 2005) Precursors of CD11c-DCs may... B-cell growth and immunoglobulin secretion (Banchereau and Steinman, 1998) DCs activate and expand T-helper cells, which in turn induce B-cell growth and antibody production (Bell et al., 1999) 14 Besides, by secretion of soluble factors, DCs stimulate the production of antibodies directly and the proliferation of B cells that have been stimulated by CD40L on activated T cells (Dubois et al., 1997) DCs... heterogeneity of human FcγRs 32 1.8 Mechanisms of antibody-mediated inflammation 34 1.9 Cellular activation by FcγRIII aggregation 38 1.10 Signaling pathways triggered by BCR-FcγRII co-ligation 38 1.11 Steps in the processing and secretion of IL-1β 50 3.1 Phenotypic properties of monocytes and moDCs 75 3.2 IL-1β and TNF-α secretion from LPS-stimulated moDCs and monocytes 77 3.3 IL-1β secretion from moDCs and. .. 2005) Precursors of CD11c-DCs may activate NK cells through the release of IFN-α, thereby leading to enhanced antiviral and antitumor activity of NK cells (Cella et al., 1997; Palucka and Banchereau, 1999b; Siegal et al., 1999) DCs at later stages of differentiation may regulate the activity of NK/NK T cells through the release of IL-12, IL-15 and IL-18 (Geldhof et al., 1998; Shah, 1987) DCs presenting... (NK) cells, phagocytic cells and interferons (IFNs) (Fearon and Locksley, 1996) Cells of the innate immune system express a restricted number of germline-encoded receptors to recognize conserved products of microbial metabolism produced by microbial pathogens (Janeway and Medzhitov, 2002) On the other hand, adaptive immunity, also known as acquired immunity, develops as a response to infection and increases... 3.4 Effect of IL-4 and GM-CSF on IL-1β secretion from LPS-stimulated monocytes 79 3.5 IL-1β secretion from LPS-stimulated moDCs and macrophages 80 3.6 IL-1β synthesis and processing by LPS-stimulated moDCs 81 3.7 IL-1β secretion from DH5α-stimulated moDCs 82 3.8 IL-1β secretion from LPS/ imIgG-co-stimulated moDCs 84 3.9 IL-1β secretion from LPS/ imIgG-co-stimulated monocytes 85 3.10 IL-1β secretion. .. This pathway allows the uptake of macromolecules through specialized regions of the plasma membrane, termed coated pits The receptors involved include C-type lectin receptors, e.g mannose receptor and DEC-205 (Engering et al., 1997; Jiang et al., 1995); Fcγ receptor typeI and II (Fanger et al., 1996); complement receptor 3 and 4 (Reis e Sousa et al., 1993), and scavenger receptors (Platt et al., 1998)... actively migrate to inflammatory site 1.2.2 Dendritic cells DCs were first described in 1868 by Paul Langerhans as the stellate-shaped epidermal cells, but mistaken for cutaneous nerve cells (Langerhans, 1868) Almost a century later, Steinman and Cohn discovered these cells in mouse spleen and applied the term dendritic cells based on their unique morphology (Steinman and Cohn, 1973) Now it is widely accepted... Effect of LPS and imIgG stimulation on IL-1β gene transcription 87 IX LIST OF FIGURES 1.1 DC development, differentiation and maturation 7 1.2 Maturation of DCs 10 1.3 In vitro monocyte-derived DC model 17 1.4 Phylogenetic tree of human TLRs 20 1.5 TIR domain-containing adaptors and TLR signaling 26 1.6 Receptor and signaling interactions during phagocytosis of microbes 30 1.7 Structural diversity and .. .INVESTIGATION OF INTERLEUKIN 1B SYNTHESIS AND SECRETION BY DENDRITIC CELLS: INTERPLAY BETWEEN TOLL-LIKE RECEPTOR AND FCG RECEPTOR WU XIAOWEI (B Sc) A THESIS SUBMITTED FOR THE DEGREE OF MASTER... responses by NK and NK T cells (Rossi and Young, 2005) Precursors of CD11c-DCs may activate NK cells through the release of IFN-α, thereby leading to enhanced antiviral and antitumor activity of NK cells. .. processing and secretion of IL-1β 50 3.1 Phenotypic properties of monocytes and moDCs 75 3.2 IL-1β and TNF-α secretion from LPS-stimulated moDCs and monocytes 77 3.3 IL-1β secretion from moDCs and monocytes