title: Blockade of tumor necrosis factor-α converting enzyme (TACE) enhances IL-1β and IFN-γ via caspase-1 activation: a probable cause for loss of efficacy of TACE inhibitors in humans?
abstract: TNF-α converting enzyme (TACE) is a member of the ADAM (a disintegrin and metalloproteinase) family and is known as ADAM17, which processes precursor TNF-α in order to release soluble TNF-α (sTNF-α). Inhibition of TACE has been effective as a strategy to inhibit arthritis in animal models; however, it has not been translated in the clinic due to lack of efficacy or toxicity. We hypothesized that inhibition of TACE may activate a different pro-inflammatory pathway in human. To investigate this, we studied the effect of TACE inhibitor DPC-333 on cytokine levels in concanavalin A (Con A) activated human peripheral blood mononuclear cells (hPBMC). We have also studied the effects of DPC-333 on Con A induced cytokine levels in mice in vivo or in vitro in whole blood assay. DPC-333 treatment significantly up-regulated IL-1β and IFN-γ in Con A activated hPBMC. In contrast, pre-treatment with DPC-333 effectively suppressed IL-1β and IFN-γ in mice in vivo or in vitro. Interestingly, DPC-333 was found to up-regulate mRNA expression of caspase-1 in hPBMC in a dose dependent fashion and selective caspase-1 inhibitor completely restored DPC-333 induced IL-1β and IFN-γ. Furthermore, selective IL-1β receptor antagonist (anakinra) prevented DPC-333 induced IFN-γ. In conclusion, our data demonstrates that blockade of TACE enhances IL-1β in a caspase-1 dependent manner in vitro in hPBMC and the elevation of IFN-γ is secondarily mediated via IL-1β. This novel finding might explain the possible cause behind the loss of efficacy of TACE inhibitors in human.
authors.affiliation: Department of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Sharma
authors.forename: Jogeswar
authors.initials: J
authors.lastname: Mohapatra
authors.forename: Aviseka
authors.initials: A
authors.lastname: Acharya
authors.forename: Shrikalp S
authors.initials: SS
authors.lastname: Deshpande
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011480:Protease Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C476910:BMS561392; D053583:Interleukin-1beta; D011480:Protease Inhibitors; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma; D020170:Caspase 1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse