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Original Article |
Correspondence to: Manuela Baccarini, Dept. of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Dr-Bohrgasse 9, 1030 Vienna, Austria. Tel:43-1-4277-54607 Fax:43-1-4277-9546 E-mail:manuela{at}gem.univie.ac.at.
Invasive Salmonella induces macrophage apoptosis via the activation of caspase-1 by the bacterial protein SipB. Here we show that infection of macrophages with Salmonella causes the activation and degradation of Raf-1, an important intermediate in macrophage proliferation and activation. Raf-1 degradation is SipB- and caspase-1–dependent, and is prevented by proteasome inhibitors. 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. Macrophages lacking c-raf-1 are hypersensitive towards pathogen-induced apoptosis. Surprisingly, activation of the antiapoptotic mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) and nuclear factor 
B pathways is normal in Raf-1–deficient macrophages, and mitochondrial fragility is not increased. Instead, pathogen-mediated activation of caspase-1 is enhanced selectively, implying that Raf-1 antagonizes stimulus-induced caspase-1 activation and apoptosis.
Key Words: serine/threonine kinase, cell death, bacteria, proteases, monocytes/macrophages
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