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Michael Naumann^*, Thomas Rudel^*, Björn Wieland^*, Cornelia Bartsch^*, and Thomas F. Meyer^*,

From the ^* Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin, Germany; and Max-Planck-Institut für Biologie, Abteilung Infektionsbiologie, 72076 Tübingen, Germany

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.

Key Words: Neisseria • inflammation • activator protein 1 • c-Jun NH₂-terminal kinase • p21-activated kinase

Abbreviations used: AP-1, activator protein 1; ASM, acidic sphingomyelinase; CRIB, Cdc42/Rac interactive binding; DAG, diacylglycerol; DN, dominant negative; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; HSP, heparan-sulfate proteoglycan; JNK, c-Jun NH₂-terminal kinase; MAP, mitogen-activated protein; MAPK, MAP kinase; MEK, MAP/ERK; MEKK, MEK kinase; MKK, MAPK kinase; MKKK, MKK kinase; MOI, multiplicities of infection; NF-B, nuclear factor B; Ngo, Neisseria gonorrhoeae; PAK, p21-activated kinase; PLC, phosphatidylcholine–dependent phospholipase C; SAPK, stress-activated protein kinase.

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