Negative feedback regulation of activated macrophages via Fas-mediated apoptosis

Apoptosis is a critical event for eliminating activated macrophages. Here w e show that Fas-mediated apoptosis may participate in the mechanism of nega tive feedback regulation of activated macrophages. Cytokine-activated macro phages released high levels of nitric oxide (NO) that induced apoptosis in macrophages themselves. This NO-induced macrophage apoptosis was inhibited by a Fas-Fc chimeric molecule that binds to Fas ligand (FasL) and prevents its interaction with endogenous cell surface Fas. High levels of NO stimula ted the release of the soluble form of FasL that was inhibited by a matrix metalloproteinase inhibitor KB-8301. High levels of NO also upregulated the expression of Fas mRNA in macrophages. In addition, macrophages isolated f rom Fas-lacking mice were resistant to NO-induced apoptosis. Finally, inhib ition of apoptosis by a caspase inhibitor augmented peroxide production fro m activated macrophages. These findings suggest that high levels of NO rele ased from activated macrophages may promote the Fas-mediated macrophage apo ptosis that may be a negative feedback mechanism for elimination and the do wnregulation of activated macrophages in the vessel wall.