© The Rockefeller University Press, 0022-1007/1997/7/247/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 2, July 21, 1997 247-258
Neisseria gonorrhoeae Epithelial Cell Interaction Leads to the Activation of the Transcription Factors Nuclear Factor
B and Activator Protein 1 and the Induction of Inflammatory Cytokines
Michael Naumann*,
Silja Weßler*,
Cornelia Bartsch*,
Björn Wieland*, and
Thomas F. Meyer*,
From the * Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin; and
Max-Planck-Institut für Biologie, Abteilung Infektionsbiologie, 72076 Tübingen, Germany
We have studied the effect of human bacterial pathogen Neisseria gonorrhoeae (Ngo) on the activation of nuclear factor (NF)-
B and the transcriptional activation of inflammatory cytokine genes upon infection of epithelial cells. During the course of infection, Ngo, the etiologic agent of gonorrhea, adheres to and penetrates mucosal epithelial cells. In vivo, localized gonococcal infections are often associated with a massive inflammatory response. We observed upregulation of several inflammatory cytokine messenger RNAs (mRNAs) and the release of the proteins in Ngo-infected epithelial cells. Moreover, infection with Ngo induced the formation of a NF-
B DNA–protein complex and, with a delay in time, the activation of activator protein 1, whereas basic leucine zipper transcription factors binding to the cAMP-responsive element or CAAT/enhancer-binding protein DNA-binding sites were not activated. In supershift assays using NF-
B–specific antibodies, we identified a NF-
B p50/p65 heterodimer. The NF-
B complex was formed within 10 min after infection and decreased 90 min after infection. Synthesis of tumor necrosis factor
and interluekin (IL)-1β occurred at later times and therefore did not account for NF-
B activation. An analysis of transiently transfected IL-6 promoter deletion constructs suggests that NF-
B plays a crucial role for the transcriptional activation of the IL-6 promoter upon Ngo infection. Inactivation of NF-
B conferred by the protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone inhibited mRNA upregulation of most, but not all, studied cyctokine genes. Activation of NF-
B and cytokine mRNA upregulation also occur in Ngo-infected epithelial cells that were treated with cytochalasin D, indicating an extracellular signaling induced before invasion.
Address correspondence to Dr. Michael Naumann, Max-Planck-Institut f ür Infektionsbiologie, Abt. Molekulare Biologie, Monbijoustr. 2, 10117 Berlin, Germany. Phone: 49-30-28026317; FAX: 49-30-28026611; E-mail: naumann{at}mpiib-berlin.mpg.de
1Abbreviations used in this paper: AP-1, activator protein 1; C/EBP, CAAT/ enhancer-binding protein; CRE, cAMP-responsive element; EMSA, electrophoretic mobility shift assay; hGH, human growth hormone; I-309, intercrine 309; MCP, monocyte chemotactic protein; MOI, multiplicity of infection; mRNA, messenger RNA; NF, nuclear factor; Ngo, Neisseria gonorrhoeae; RT-PCR, reverse transcriptase PCR; TPCK, N-tosyl-L-phenylalanine-chloromethyl ketone.

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