test Browse by Author Names Browse by Titles of Works Browse by Subjects of Works Browse by Issue Dates of Works
       

Advanced Search
Home   
 
Browse   
Communities
& Collections
  
Issue Date   
Author   
Title   
Subject   
 
Sign on to:   
Receive email
updates
  
My Account
authorized users
  
Edit Profile   
 
Help   
About T-Space   

T-Space at The University of Toronto Libraries >
School of Graduate Studies - Theses >
Doctoral >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/17796

Title: Regulation of Toll-like Receptor Signal Transduction Pathways
Authors: Lu, Yong-Chen
Advisor: Ohashi, Pamela S.
Department: Medical Biophysics
Keywords: TLR
Issue Date: 24-Sep-2009
Abstract: The stimulation of Toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) activates macrophages and dendritic cells to response to pathogens. These activated cells induce many immune-related genes, including proinflammatory cytokines which are necessary to activate immune responses against infection. TLRs and their signaling components have been linked to several human diseases, including pyogenic infection and sepsis. Sepsis often occurs in cancer patients treated with chemotherapy. The first focus of this work is to understand how TLR signal transduction pathways regulate the induction of proinflammatory cytokines. TLR stimulation triggers a signaling pathway via MyD88 and IRAK-4 that is essential for proinflammatory cytokine induction. In this study, I found that MyD88-deficient macrophages had defective c-Rel activation, which has been linked to IL-12 p40 induction. In addition, the expression of C/EBPbeta and C/EBPdelta was limited in MyD88- or IRAK-4-deficient macrophages treated with LPS. Importantly, the absence of both C/EBPbeta and C/EBPdelta resulted in the impaired induction of proinflammatory cytokines stimulated by several TLR ligands. These results identify both c-Rel and C/EBPbeta/delta as important transcription factors in a MyD88-dependent pathway that regulate the induction of proinflammatory cytokines. The second focus of this work is to understand the function of TREM2 and how TREM2 regulates TLR-mediated immune responses. TREM2 and DAP12 deficiencies were found in human patients with Nasu-Hakola disease, but the biology of TREM2 remains unclear. To study the function of TREM2 in dendritic cells, TREM2-deficient mice were generated. I found that TREM2 down-regulated the expression of proinflammatory cytokines induced by TLRs. The TREM2 ligand was expressed on activated T cells, and TREM2 enhanced the expression of IFN-gamma in antigen-specific T cells. In a mouse model of autoimmune diabetes, TREM2-deficient mice were resisted to CD8+ T cell-mediated beta-cell destruction. Therefore, TREM2 can positively or negatively regulate TLR-mediated immune responses in selective conditions. Together, the results presented in this thesis provide further understanding of how c-Rel, C/EBPbeta/delta, and TREM2 control and modulate TLR-mediated responses. Understanding these processes may ultimately provide novel therapeutic strategies to modulate immune responses in patients suffered from infectious diseases and cancer.
URI: http://hdl.handle.net/1807/17796
Appears in Collections:Doctoral
Department of Medical Biophysics - Doctoral theses

Files in This Item:

File Description SizeFormat
Lu_YongChen_200906_PhD_thesis.pdf3.8 MBAdobe PDF
View/Open

This item is licensed under a Creative Commons License
Creative Commons

Items in T-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

uoft