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J. Exp. Med.,
Volume 188, Number 7, October 5, 1998 1277-1286
By
From the * Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin,
Germany; and 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 Biologie, Abteilung Infektionsbiologie, 72076 Tübingen, Germany
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