Yersinia enterocolitica Promotes Deactivation of Macrophage Mitogen-activated Protein Kinases Extracellular Signal-regulated Kinase-1/2, p38, and c-Jun NH2-terminal Kinase

Abstract

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-␣ (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 NH 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␣ 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.

Targeting Rac1 by the Yersinia Effector Protein YopE Inhibits Caspase-1-mediated Maturation and Release of Interleukin-1β

“…Until recently, four of the six injected effectors of Yersinia were believed to target elements of the cytoskeleton to block phagocytosis. However, recent reports illustrated that some of the anti-phagocytic effectors such as YopH can also interfere with signaling pathways of the immune defense system, leading to a down-regulation of the F c -mediated oxidative burst in macrophages and neutrophils, for example (12,46,47). The caspase-1 inhibitory effect of YopE described in this study revealed a novel function of Yop effector proteins in regulating the inflammatory response against Yersinia infection.…”

IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes

“…Lysates were then mixed with GST fusion protein kinase substrates (2.5 mg of each, as indicated) and gluthathione-sepharose (15 ml, Amersham) and incubated at 48C overnight. Experiments were carried out as described (Ruckdeschel et al, 1997) with two dierent GST fusion protein kinase substrates obtained from M Karin (GST-c-jun (1 ± 222), and B De ridjard (GST-ATF-2). After pull-down, beads were washed four times with binding buer (20 mM HEPES, pH 7.7, 50 mM NaCl, 25 mM MgCl 2 , 0.1 mM EDTA, 0.05% Triton X-100), and in vitro phosphorylation was carried out for at 308C for 20 min in 30 ml of kinase buer containing, 20 mM HEPES, pH 7.6, 20 mM MgCl 2 , 20 mM b-glycerophosphate, 0.1 mM Na 3 VO 4 , 2 mM DTT, 20 mM p-nitrophenylphosphate, 20 mM ATP (4 mCi of [g-32 P]ATP).…”

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

“…Meanwhile, increasing evidence suggests that bacterial pathogens target and manipulate those signaling pathways for their benefits (12). For example, Yersinia enterocolitica was indicated to suppress TNF production by inhibiting ERK1/2, p38, and JNK activities (13). Macrophages infected with Mycobacterium avium showed decreased MAPK activation compared with the cells infected with nonpathogenic mycobacteria (14).…”