Abstract
The virulence-associated V Ag (LcrV) of pathogenic Yersinia species is part of the translocation apparatus, required to deliver antihost effector proteins (Yersinia outer proteins) into host cells. An orthologous protein (denoted as PcrV) has also been identified in the ExoS regulon of Pseudomonas aeruginosa. Additionally, it is known that LcrV is released by yersiniae into the environment and that LcrV causes an immunosuppressive effect when injected into mice. In this study, we demonstrate for the first time that rLcrV, but not PcrV, is capable of suppressing TNF-alpha production in zymosan A-stimulated mouse macrophages and the human monocytic Mono-Mac-6 cell line. The underlying mechanism of TNF-alpha suppression could be assigned to LcrV-mediated IL (IL)-10 production, because 1) LcrV induces IL-10 release in macrophages, 2) anti-IL-10 Ab treatment completely abrogated TNF-alpha suppression, and 3) TNF-alpha suppression was absent in LcrV-treated macrophages of IL-10-deficient (IL-10-/-) mice. The relevance of LcrV-mediated immunosuppression for the pathogenicity of yersiniae became evident by experimental infection of mice; in contrast to wild-type mice, IL-10-/- mice were highly resistant against Yersinia infection, as shown by lower bacterial load in spleen and liver, absent abscess formation in these organs, and survival.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / antagonists & inhibitors
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Adjuvants, Immunologic / pharmacology
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Animals
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Antibodies, Bacterial / pharmacology
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Antigens, Bacterial / administration & dosage
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Antigens, Bacterial / genetics
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Antigens, Bacterial / immunology*
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Antigens, Bacterial / pharmacology
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Bacterial Toxins / immunology
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Bacterial Toxins / pharmacology
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Cell Line
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Dose-Response Relationship, Immunologic
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Female
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Humans
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Immune Sera / pharmacology
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Immunity, Innate / genetics
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Interleukin-10 / biosynthesis*
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Interleukin-10 / deficiency
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Interleukin-10 / genetics*
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Interleukin-10 / immunology
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / metabolism*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / immunology
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Monocytes / metabolism
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Pore Forming Cytotoxic Proteins
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Recombinant Proteins / administration & dosage
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Survival Rate
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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Virulence
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Yersinia Infections / genetics
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Yersinia Infections / immunology
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Yersinia Infections / mortality
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Yersinia enterocolitica / immunology*
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Yersinia enterocolitica / pathogenicity
Substances
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Adjuvants, Immunologic
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Antibodies, Bacterial
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Antigens, Bacterial
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Bacterial Toxins
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Immune Sera
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LcrV protein, Yersinia
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Pore Forming Cytotoxic Proteins
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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antigen V, Pseudomonas
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Interleukin-10