Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures.

Abstract

We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down-stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases.

• Authors: L M Williams, D L Gibbons, A Gearing, R N Maini, M Feldmann, F M Brennan
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 97 Issue 12 Pg. 2833-41 (Jun 15 1996) ISSN: 0021-9738 [Print] United States
• PMID: 8675695 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BB 2275
• Hydroxamic Acids
• Protease Inhibitors
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Metalloendopeptidases

Topics

• Arthritis, Rheumatoid (metabolism)
• Cell Line
• Humans
• Hydroxamic Acids (pharmacology)
• Metalloendopeptidases (antagonists & inhibitors)
• Protease Inhibitors (pharmacology)
• Receptors, Tumor Necrosis Factor (antagonists & inhibitors)
• Rhabdomyosarcoma (pathology)
• Synovial Membrane (metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, pharmacology)