Item – Theses Canada

OCLC number
1032966116
Link(s) to full text
LAC copy
Author
Sharma, Mehul.
Title
Extracellular Granzyme K mediates endothelial inflammation through the cleavage of Protease Activated Receptor-1.
Degree
(Master of Science - MSc)--University of British Columbia, 2015.
Publisher
Vancouver : University of British Columbia, 2015.
Description
1 online resource
Notes
Includes bibliographical references.
Http://creativecommons.org/licenses/by-nc-nd/2.5/ca.
Attribution-NonCommercial-NoDerivs 2.5 Canada.
Abstract
Granzymes are a family of serine proteases that were once thought to function exclusively as mediators of cytotoxic lymphocyte-induced target cell death. However, non-lethal roles for granzymes, including Granzyme K (GzK), have been recently proposed. As recent studies have observed elevated levels of GzK in plasma of patients diagnosed with sepsis, we hypothesized that extracellular GzK induces a pro-inflammatory response in endothelial cells. In the present study, extracellular GzK proteolytically activated Protease Activated Receptor-1 (PAR-1) leading to increased IL-6 and MCP-1 production in Human Umbilical Venous Endothelial Cells (HUVEC). Enhanced expression of ICAM-1 along with an increased capacity for adherence of THP-1 cells was also observed. Characterization of downstream pathways implicated the MAPK p38 pathway for ICAM-1 expression, and both the p38 and the ERK1/2 pathways in cytokine production. GzK also increased TNF[alpha]-induced inflammatory adhesion molecule expression. Furthermore, the physiological inhibitor of GzK, I[alpha]Ip, significantly inhibited GzK activity in vitro. In summary, extracellular GzK is not cytotoxic but promotes a pro-inflammatory response in endothelial cells.
Other link(s)
hdl.handle.net
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