Innate leukocytes manifest dynamic and distinct inflammatory responses upon challenges with rising dosages of pathogen associated molecular pattern molecules (PAMPs) such as lipopolysaccharide (LPS). To differentiate signal strengths, innate leukocytes may utilize distinct intra-cellular signaling circuitries modulated by adaptor molecules. Toll-interacting protein (Tollip) is one of the critical adaptor molecules in Toll-like receptor 4 (TLR4) signaling and potentially playing key roles in modulating the dynamic adaptation of innate leukocytes to varying dosages of external stimulants. While Tollip may serve as a negative regulator of NFkB signaling pathway in cells challenged with higher dosages of LPS, it acts as a positive regulator for low-grade chronic inflammation in leukocytes programmed by subclinical low-dosages of LPS. We aim to show recent progress in our understanding of complex innate leukocyte dynamics and its relevance in the pathogenesis of resolving versus non-resolving chronic inflammatory diseases. / Ph. D. / White blood cells, or leukocytes, have a dynamic inflammatory response to rising doses of bacterial cell wall components. Lipopolysaccharide (LPS) is a ubiquitous component of gram negative bacteria that is recognized by Toll-like receptor 4 (TLR4) and can shed into the blood stream, causing low-grade non-resolving inflammation. In order to differentiate between varying signal strengths of LPS, leukocytes utilize signaling within the cell, which is often regulated by adaptor molecules. Toll-interacting protein (Tollip) is one of the critical adaptor molecules in TLR4 signaling and potentially plays key roles in modulating the dynamic adaptation of innate leukocytes to varying dosages of external stimulants. While Tollip serves to inhibit the pro-inflammatory NFκB signaling in cells challenged with higher dosages of LPS, it acts to increase low-grade chronic inflammation in leukocytes programmed by low-dosages of LPS. In these studies we show recent progress in elucidating the mechanism for Tollip involvement in low-grade non-resolving inflammation in mouse fibroblast cells.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/78340 |
| Date | 13 July 2017 |
| Creators | Kowalski, Elizabeth Ashley |
| Contributors | Biochemistry, Li, Liwu, Bevan, David R., Helm, Richard F., Xu, Bin |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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