Yersinia enterocolitica promotes deactivation of macrophage mitogen-activated protein kinases extracellular signal-regulated kinase-1/2, p38, and c-Jun NH sub(2)-terminal kinase. Correlation with its inhibitory effect on tumor necrosis factor- alpha production

• Published in: The Journal of biological chemistry 1997-06, Vol.272 (25), p.15920-15927
• Main Authors: Ruckdeschel, K, Machold, J, Roggenkamp, A, Schubert, S, Pierre, J, Zumbihl, R, Liautard, J-P, Heesemann, J, Rouot, B
• Format: Article
• Language: English
• Subjects: Yersinia enterocolitica
• ISSN: 0021-9258

The enteropathogenic bacterium Yersinia enterocolitica counteracts host defense mechanisms by interfering with eukaryotic signal transduction pathways. In this study, we investigated the mechanism by which Y. enterocolitica prevents macrophage tumor necrosis factor- alpha (TNF alpha ) production. Murine J774A.1 macrophages responded to Y. enterocolitica infection by rapid activation of mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase (ERK), p38, and c-Jun NH sub(2)-terminal kinase (JNK). However, after initial activation, the virulent Y. enterocolitica strain harboring the Y. enterocolitica virulence plasmid caused a substantial decrease in ERK1/2 and p38 tyrosine phosphorylation. Simultaneously, the virulent Y. enterocolitica strain gradually suppressed phosphorylation of the transcription factors Elk-1, activating transcription factor 2 (ATF2), and c-Jun, indicating time-dependent inhibition of ERK1/2, p38, and JNK kinase activities, respectively. Analysis of different Y. enterocolitica mutants revealed that (i) MAPK inactivation parallels the inhibition of TNF alpha release, (ii) the suppressor effect on TNF alpha production, which originates from the lack of TNF alpha mRNA, is distinct from the ability of Y. enterocolitica to resist phagocytosis and to prevent the oxidative burst, (iii) the tyrosine phosphatase YopH, encoded by the Y. enterocolitica virulence plasmid, is not involved in the decrease of ERK1/2 and p38 tyrosine phosphorylation or in the cytokine suppressive effect. Altogether, these results indicate that Y. enterocolitica possesses one or more virulence proteins that suppress TNF alpha production by inhibiting ERK1/2, p38, and JNK kinase activities.