title: Distinct mechanisms target stress and extracellular signal-activated kinase 1 and Jun N-terminal kinase during infection of macrophages with Salmonella.
abstract: 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 zeta. 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.
authors.affiliation: Department of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Austria.
authors.forename: K J
authors.initials: KJ
authors.lastname: Procyk
authors.forename: M R
authors.initials: MR
authors.lastname: Rippo
authors.forename: R
authors.initials: R
authors.lastname: Testi
authors.forename: F
authors.initials: F
authors.lastname: Hoffmann
authors.forename: P J
authors.initials: PJ
authors.lastname: Parker
authors.forename: M
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D047029:Lactams, Macrocyclic; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology; D011493:Protein Kinase C / Q000502:physiology; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D012486:Salmonella typhimurium / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology; D014162:Transfection; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D010738:Type C Phospholipases; D013108:Sphingomyelin Phosphodiesterase; C105598:phosphatidylcholine-specific phospholipase C; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins