The novel regulation of Toll-Like Receptor 4

• Main Authors: Ting-Yu Lai, 賴亭諭
• Other Authors: 徐立中
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/02895982128757847444

博士 === 國立臺灣大學 === 分子醫學研究所 === 103 === In mammals, innate immunity is the first line of defense against pathogenic infection, and is mainly mediated by pattern-recognition receptors, including Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns derived from microbes or endogenous molecules termed damage-associated molecular patterns. Macrophages, a type of phagocytic leukocytes, play a crucial role in innate immunity by producing various cytokines and chemokines and presenting antigens to lymphocytes, both of which are also involved in the activation of adaptive immunity. However, dysregulation of TLRs-mediated inflammatory response can impair host immune homeostasis, and is associated with many autoimmune and inflammatory diseases, such as systemic inflammatory response syndrome (SIRS) and atherosclerosis. Thus, the molecular mechanisms of how TLRs signaling is regulated have been intensively investigated, but the detailed mechanism still remains fragmentary. In this study, we discovered two novel regulatory mechanisms in TLR4-mediated immune response by exploring microarray analysis. We found that TLR4 engagement induced a transcription factor C/EBPβ through p38 MAPK, which subsequently increased A20 expression in conjunction with NF-κB. A20, in turn, negatively regulated TLR4 signaling to terminate inflammatory response. In addition, we identified a novel E3 ubiquitin ligase, ZNRF1, which mediated caveolin-1 (CAV1) ubiquitination and degradation in response to lipopolysaccharide (LPS). Mechanistically, the ZNRF1-CAV1 axis influences Akt-GSK3β activity upon TLR4 activation, eventually resulting in enhanced production of pro-inflammatory cytokines and inhibiting anti-inflammatory cytokine IL-10 expression. Our findings unravel two new regulatory mechanisms of TLR4 signaling pathway and may shed light on treatments for inflammation-related diseases.