Distinct mechanisms target stress and extracellular signal-activated kinase 1 and jun N-terminal kinase during infection of macrophages with Salmonella

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. C ytokines produced by infected macrophages are involved in the early gastroi ntestinal pathology of the infection as well as in the induction and mainte nance of the immune response against the invaders. Jun N-terminal kinases ( JNK) are activated by inflammatory stimuli and play a role in cytokine prod uction. We have investigated the signaling routes leading to JNK activation in Salmonella-infected macrophages and have discovered that they differ ra dically from the mechanisms operating in epithelial cells. In particular, a ctivation of the JNK kinase stress and extracellular-activated kinase 1 (SE K1) and of JNK in macrophages occurs independently of actin rearrangements and of the GTPases Cdc42 and Rac, essential mediators in other cells. Activ ation of JNK is effected by a novel pathway comprising tyrosine kinase(s), phosphoinositide 3-kinase and, likely, atypical protein kinase C zeta. SEK1 is stimulated by a distinct mechanism involving phosphatidylcholine-phosph olipase 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 direc t the selective coupling of downstream pathways to elicit highly specific r esponses. Inhibitors of stress kinase pathways are receiving increasing att ention as potential anti-inflammatory drugs. The precise reconstruction of stimulus-specific pathways will be instrumental in predicting/evaluating th e effects of the inhibitors on a given pathological condition.