Unlike For Human Monocytes After Lps Activation, Release Of Tnf-Alpha By Thp-1 Cells Is Produced By A Tace Catalytically Different From Constitutive Tace

Background: Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-alpha, initially synthesized as a membrane-anchored precursor (pro-TNF-alpha), is processed by proteolytic cleavage to generate the secreted mature form. TNF-alpha converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-alpha.Methodology/Principal Findings: Here, we demonstrated the presence on THP-1 cells as on human monocytes of a constitutive proteolytical activity able to cleave pro-TNF-alpha. 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-alpha 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-alpha release in LPS activated THP-1 cells, by contrast to human monocytes where the TACE activity remains catalytically unchanged even after LPS activation.Conclusions/Significance: On the surface of LPS activated THP-1 cells we identified a releasing TNF-alpha 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.