title: Unlike for human monocytes after LPS activation, release of TNF-α by THP-1 cells is produced by a TACE catalytically different from constitutive TACE.
abstract: BACKGROUND
  Tumor 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.
  
  
  RESULTS
  Here, 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
  On 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.
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France. heltab@basmed.am.wroc.pl
authors.forename: Helena
authors.initials: H
authors.lastname: Moreira-Tabaka
authors.forename: Jean
authors.initials: J
authors.lastname: Peluso
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vonesch
authors.forename: Didier
authors.initials: D
authors.lastname: Hentsch
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Reimund
authors.forename: Serge
authors.initials: S
authors.lastname: Dumont
authors.forename: Christian D
authors.initials: CD
authors.lastname: Muller
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D009000:Monocytes / Q000166:cytology*; D053978:Pentacyclic Triterpenes; D010447:Peptide Hydrolases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C459386:2-(1-(hydroxycarbamoyl)-4-phenyl-3-butenyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide; D016227:Benzoquinones; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D053978:Pentacyclic Triterpenes; D011994:Recombinant Proteins; D013449:Sulfonamides; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D010447:Peptide Hydrolases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C050414:celastrol; C003466:thymoquinone