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.