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(Received for publication, November 19, 1996, and in revised form, March 3, 1997)
From 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-
Volume 272, Number 25,
Issue of June 20, 1997
pp. 15920-15927
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
CORRELATION WITH ITS INHIBITORY EFFECT ON TUMOR NECROSIS
FACTOR-
PRODUCTION
,
,
,
,
INSERM U431, Université Montpellier II,
Place E. Bataillon, CC100, F-34095 Montpellier Cedex 05, France,
¶ INSERM U461, Faculté de Pharmacie, 92296 Châtenay-Malabry Cedex, France, and § Max von
Pettenkofer-Institut für Hygiene und Mikrobiologie,
Pettenkoferstrasse 9a, D-80336 München, Germany
(TNF) 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
NH2-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 release, (ii) the suppressor effect
on TNF production, which originates from the lack of TNF 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
production by inhibiting ERK1/2, p38, and JNK kinase activities.
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