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*
Department of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Vienna, Austria;
Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy;
Institut für Pharmakologie und Toxikologie, Freiburg, Germany; and
§
Protein Phosphorylation Lab, Imperial Cancer Research Fund, London United Kingdom
The interaction between bacteria and macrophages is central to the
outcome of Salmonella infections.
Salmonella can escape killing by these phagocytes and
survive and multiply within them, giving rise to chronic infections.
Cytokines produced by infected macrophages are involved in the early
gastrointestinal pathology of the infection as well as in the induction
and maintenance of the immune response against the invaders. Jun
N-terminal kinases (JNK) are activated by inflammatory stimuli and play
a role in cytokine production. We have investigated the signaling
routes leading to JNK activation in Salmonella-infected
macrophages and have discovered that they differ radically from the
mechanisms operating in epithelial cells. In particular, activation of
the JNK kinase stress and extracellular-activated kinase 1 (SEK1) and
of JNK in macrophages occurs independently of actin rearrangements and
of the GTPases Cdc42 and Rac, essential mediators in other cells.
Activation of JNK is effected by a novel pathway comprising tyrosine
kinase(s), phosphoinositide 3-kinase and, likely, atypical protein
kinase C 
. SEK1 is stimulated by a distinct mechanism involving
phosphatidylcholine-phospholipase C and acidic sphingomyelinase.
Dominant-negative SEK1 can block JNK activation by LPS, but not by
Salmonella. These data demonstrate that SEK1 and JNK are
activated independently in Salmonella-infected
macrophages and offer experimental support for the concept that
incoming signals can direct the selective coupling of downstream
pathways to elicit highly specific responses. Inhibitors of stress
kinase pathways are receiving increasing attention as potential
anti-inflammatory drugs. The precise reconstruction of
stimulus-specific pathways will be instrumental in
predicting/evaluating the effects of the inhibitors on a given
pathological condition.
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