Coordinate activation of activator protein 1 and inflammatory cytokines in response to Neisseria gonorrhoeae epithelial cell contact involves stress response kinases.
Neisseria gonorrhoeae (Ngo), the etiologic agent of gonorrhea, induce a number of proinflammatory cytokines by contact to epithelial cells. Cytokine genes and a variety of other immune response genes are activated as a result of the regulatory function of immediate early response transcription factors including activator protein 1 (AP-1). Since it is established that phosphorylation of c-Jun, the central component of AP-1, by the stress-activated c-Jun NH2-terminal kinase (JNK) increases the transcriptional activity of AP-1, we studied whether Ngo could induce stress response pathways involving JNK. We found that virulent Ngo strains induce phosphorylation and activation of JNK but not of p38 kinase. Analysis of a nonpathogenic Ngo strain revealed only weak JNK activation. In respect to the molecular components upstream of the JNK signaling cascade, we show that a dominant negative mutant of MAP kinase kinase 4 (MKK4) represses transcription of an AP-1-dependent reporter gene. Regarding upstream stress response factors involved in Ngo-induced MKK4/JNK/AP-1 activation, we identified p21-activated kinase (PAK) but not MAPK/ERK kinase kinase (MEKK1). Inhibition of small GTPases including Rac1 and Cdc42 by Toxin B prevented JNK and AP-1 activation. Our results indicate that Ngo induce the activation of proinflammatory cytokines via a cascade of cellular stress response kinases involving PAK, which directs the signal from the Rho family of small GTPases to JNK/AP-1 activation.
Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin, Germany. naumann@mpiib-berlin.mpg.de
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Naumann
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Rudel
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Wieland
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Bartsch
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Meyer
D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009344:Neisseria gonorrhoeae / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D054462:p21-Activated Kinases
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D016207:Cytokines; D018808:Transcription Factor AP-1; C031815:toxB protein, Clostridium difficile; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases