Article Text
Abstract
Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor α (TNFα) in inflammatory diseases. As a result of this work, a number of biological agents that neutralise the activity of this cytokine have entered the clinic. The recent clinical data obtained with etanercept and infliximab highlight the relevance of this strategy. TNFα converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNFα (proTNFα) to the 17 kDa soluble component. Although a number of proteases have been shown to process proTNFα, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinical development. These inhibitors effectively block TACE mediated processing of proTNFα and can reduce TNF production by lipopolysaccharide stimulated whole blood by >95%. Through a series of studies it is shown here that >80% of the unprocessed proTNFα is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitro, TACE inhibition has also been implicated in shedding of p55 and p75 surface TNFα receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibitors are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNFα. In many studies greater efficacy is observed with the TACE inhibitors, presumably owing to greater penetration to the site of TNFα production.
- tumour necrosis factor α
- tumour necrosis factor convertase
- ADAM-17
- inflammation
Abbreviations
- ADAM = A disintegrin and a metalloproteinase-containing enzyme
- CIA = collagen-induced arthritis
- IL1
- 6 = interleukin 1, 6
- IP = intraperitoneal
- LPS = bacterial lipopolysaccharide
- MMP = matrix metalloproteinase
- proTNFα = precursor form for TNFα
- TACE = TNFα converting enzyme
- TNFα = tumour necrosis factor α
- TNFR = tumour necrosis factor receptor
- TSST-1 = toxic shock syndrome toxin-1
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Abbreviations
- ADAM = A disintegrin and a metalloproteinase-containing enzyme
- CIA = collagen-induced arthritis
- IL1
- 6 = interleukin 1, 6
- IP = intraperitoneal
- LPS = bacterial lipopolysaccharide
- MMP = matrix metalloproteinase
- proTNFα = precursor form for TNFα
- TACE = TNFα converting enzyme
- TNFα = tumour necrosis factor α
- TNFR = tumour necrosis factor receptor
- TSST-1 = toxic shock syndrome toxin-1