Kendall M. Mohler

Further evidence for a common mechanism for shedding of cell surface proteins

Pro‐TNFα, Steel factor, type II IL‐1R and IL‐2Rα were expressed in COS‐7 cells and the generation of their soluble forms was examined. The release of all four proteins was strongly stimulated by the phorbol ester PMA and completely blocked by a hydroxamate‐based inhibitor of metalloproteases. COS‐7 cell membranes were found to cleave various synthetic pro‐TNFα peptides with the same specificity as a partially purified TNFα converting enzyme purified from human monocytic cells, suggesting that the same enzyme may be responsible for at least some of the COS‐7 cell shedding activity.

Chapter 24. Agents that Block TNF-α Synthesis or Activity

Publisher Summary The therapeutic utility of tumor necrosis factor-α (TNF-α)-neutralizing agents has been proven in studies with specific TNF-α-binding proteins. TNF-α is a cytokine that appears rapidly in response to infection and trauma. Its main physiological function appears to be mobilizing the host defense. This chapter discusses the more recent inhibitors of TNFα production and signaling on the structure and function of TNF-α converting enzyme (TACE) and on proteins that prevent TNF-α from binding to cell-surface receptors. Many of the compounds discussed in the chapter, including the cytokine-suppressing anti-inflammatory drugs (CSAIDS), affect the expression or signaling of multiple cytokines. Blocking inflammatory cytokines (IL-1 and IL-6) as well as TNF-α may increase a compounds anti-inflammatory potential or it may generate deleterious side-effects. Other blockers of TNF-α production, such as the adenosine receptor agonists, the phosphodiesterase inhibitors, and thalidomide derivatives, do not affect other inflammatory cytokines. Adenosine (Ado) or MDLZO111Z, a related carbocyclic nucleoside, inhibit the production of TNF-α from activated mouse peritoneal macrophages and from macrophage cell lines. MDLZO111Z inhibits the expression of steady-state TNF-α messenger RNA (mRNA) in the cell lines, but adenosine (Ado) does not, suggesting that the latter block TNF-α synthesis at a post-transcriptional level. It is not clear that Ado receptor mediates these effects on TNF production.