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Title: The regulation of tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) during acute inflammation
Author: Scott, Alasdair James
ISNI:       0000 0004 2693 8566
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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The systemic inflammatory response syndrome (SIRS) describes the immune response to an insult that is inappropriate for a patient’s biological needs. Tumour necrosis factor-α (TNF) is one of the principal pro-inflammatory cytokines that mediates SIRS. TNF-α converting enzyme (TACE) is responsible for the ectodomain cleavage of numerous immunologically relevant substrates including TNF, both TNF receptors and the cellular adhesion molecule L-selectin. The biological significance of TACE lays in its ability to control the availability of these key mediators of the immune response in their membrane-bound and soluble forms. Little is known concerning the regulation of TACE-mediated ectodomain shedding and it contributes to disease pathophysiology. Our objective was to investigate the regulation of TACE catalytic activity and expression during acute inflammation in vitro and in vivo. Our aims were: 1) define the pathways mediating upregulation of TACE activity in primary human monocytes; 2) compare the regulation of TACE catalytic activity and TACE substrate shedding; 3) investigate the acute inflammatory response in elective surgical patients with particular focus on three potential biomarkers of inflammation: TACE expression, HLA-DR expression and circulating monocyte subset populations. We used a fluorimetric assay of TACE activity to demonstrate that lipopolysaccharide (LPS) stimulation of primary human monocytes promotes rapid upregulation of TACE activity, independently of changes in TACE expression. TACE activity upregulation was mediated by reactive oxygen species-induced activation of the p38 MAPK-MK2 pathway. Dithiol oxidation was found to induce L-selectin shedding but to attenuate LPS-induced TACE activity upregulation. Investigation of this paradox revealed that L-selectin shedding may be independent of TACE activity upregulation. Monocyte TACE expression was not modified by low to intermediate risk surgery. In contrast, surgery resulted in downregulation of monocyte HLA-DR expression and differential trafficking of monocyte subsets. These data provide insight into the regulation of TACE during acute inflammation.
Supervisor: Takata, Masao ; O'Dea, Kieran Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral