Abstract
BackgroundTumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-α, initially synthesized as a membrane-anchored precursor (pro-TNF-α), is processed by proteolytic cleavage to generate the secreted mature form. TNF-α converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-α.Methodology/Principal FindingsHere, we demonstrated the presence on THP-1 cells as on human monocytes of a constitutive proteolytical activity able to cleave pro-TNF-α. Revelation of the cell surface TACE protein expression confirmed that the observed catalytic activity is due to TACE. However, further studies using effective and innovative TNF-α inhibitors, as well as a highly selective TACE inhibitor, support the presence of a catalytically different sheddase activity on LPS activated THP-1 cells. It appears that this catalytically different TACE protease activity might have a significant contribution to TNF-α release in LPS activated THP-1 cells, by contrast to human monocytes where the TACE activity remains catalytically unchanged even after LPS activation.Conclusions/SignificanceOn the surface of LPS activated THP-1 cells we identified a releasing TNF-α activity, catalytically different from the sheddase activity observed on human monocytes from healthy donors. This catalytically-modified TACE activity is different from the constitutive shedding activity and appears only upon stimulation by LPS.
Highlights
Tumor Necrosis Factor-a (TNF-a) is a pro-inflammatory cytokine produced and secreted primarily by macrophages and monocytes in response to a bacterial challenge or tumor burden
First we aimed to assess their anti-Tumor necrosis factor-alpha (TNF-a) potency in our cell-based inflammation models: human mononuclear cells isolated from peripheral blood (PBMCs), human monocytes purified from peripheral blood (PBMs) and the human monocytic cell line (THP-1)
In our hands and in accordance with Shutery et al report, the selective TNF-a converting enzyme (TACE) inhibitor Ro 32-7315 significantly increased the number of cells bearing high m-TNF-a levels in LPS activated THP-1 cells as well as in PBMC
Summary
Tumor Necrosis Factor-a (TNF-a) is a pro-inflammatory cytokine produced and secreted primarily by macrophages and monocytes in response to a bacterial challenge or tumor burden. Large amounts of TNF-a are released in response to lipopolysaccharide (LPS) and other bacterial products (e.g. staphylococcal enterotoxin B, bacterial super antigen toxin 1). It is well established that the induction of TNF-a production upon stimulation by LPS results from both an enhancement of TNF-a gene transcription and a translational derepression of its mRNA. The newly synthesized TNF-a protein initially accumulates primarily within the Golgi complex and goes through the secretory pathway up to the cell surface [3]. Tumor necrosis factor-alpha (TNF-a) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-a converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-a
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