Yersinia enterocolitica Impairs Activation of Transcription Factor NF- k B: Involvement in the Induction of Programmed Cell Death and in the Suppression of the Macrophage Tumor Necrosis Factor a Production

In this study, we investigated the activity of transcription factor NFk B in macrophages infected with Yersinia enterocolitica. Although triggering initially a weak NFk B signal, Y. enterocolitica inhibited NFk B activation in murine J774A.1 and peritoneal macrophages within 60 to 90 min. Simultaneously, Y. enterocolitica prevented prolonged degradation of the inhibitory proteins I k Ba and I k Bb observed by treatment with lipopolysaccharide (LPS) or nonvirulent, plasmid-cured yersiniae. Analysis of different Y. enterocolitica mutants revealed a striking correlation between the abilities of these strains to inhibit NFk B and to suppress the tumor necrosis factor a (TNFa ) production as well as to trigger macrophage apoptosis. When NFk B activation was prevented by the proteasome inhibitor MG-132, nonvirulent yersiniae as well as LPS became able to trigger J774A.1 cell apoptosis and inhibition of the TNFa secretion. Y. enterocolitica also impaired the activity of NFk B in epithelial HeLa cells. Although neither Y. enterocolitica nor TNFa could induce HeLa cell apoptosis alone, TNFa provoked apoptosis when activation of NFk B was inhibited by Yersinia infection or by the proteasome inhibitor MG132. Together, these data demonstrate that Y. enterocolitica suppresses cellular activation of NFk B, which inhibits TNFa release and triggers apoptosis in macrophages. Our results also suggest that Yersinia infection confers susceptibility to programmed cell death to other cell types, provided that the appropriate death signal is delivered.