Protective role of Raf-1 in Salmonella-induced macrophage apoptosis

Invasive Salmonella induces macrophage apoptosis via the activation of casp ase-1 by the bacterial protein SipB. Here we show that infection of macroph ages with Salmonella causes the activation and degradation of Raf-1, an imp ortant intermediate in macrophage proliferation and activation. Raf-1 degra dation is SipB- and caspase-1-dependent, and is prevented by proteasome inh ibitors. To study the functional significance of Raf-1 in this process, the c-raf-1 gene was inactivated by Cre-loxP-mediated recombination in vivo. M acrophages lacking c-raf-1 are hypersensitive towards pathogen-induced apop tosis. Surprisingly, activation of the antiapoptotic mitogen-activated prot ein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and nuc lear factor kappaB pathways is normal in Raf-1-deficient macrophages, and m itochondrial fragility is not increased. Instead, pathogen-mediated activat ion of caspase-1 is enhanced selectively, implying that Raf-1 antagonizes s timulus-induced caspase-1 activation and apoptosis.