Yersinia enterocoliticaEvasion of the Host Innate Immune Response by V Antigen-Induced IL-10 Production of Macrophages Is Abrogated in IL-10-Deficient Mice

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-α production in zymosan A-stimulated mouse macrophages and the human monocytic Mono-Mac-6 cell line. The underlying mechanism of TNF-α 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-α suppression, and 3) TNF-α 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.

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“…IL-10 is a cytokine with broad antiinflammatory properties that results from its ability to inhibit functions of both macrophages and dendritic cells, including secretion of their proinflammatory cytokines [24] and NO production [25]. Sing et al [26] reported that low calcium response V (LcrV) or antigen V, a secreted antihost protein with strong immunomodulatory effects that is associated Yersinia virulence, inhibits zymosan-induced production of TNF-a by inducing IL-10. The increase of IL-10 production, in the early period of infection, was consistent with the observed decrease of proinflammatory cytokines and NO production in the same period.…”

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“…Thus, pretreatment of wildtype peritoneal macrophages with recombinant LcrV (rLcrV) inhibited zymosan induced TNF-production. The anti-inflammatory effect of macrophages was found to be IL-10 dependent because it could be reversed by neutralizing antibodies specific to IL-10.There was no effect of neutralizing antibodies against IL-4 or TGF-, two other cytokines known to inhibit inflammatory responses of macrophages (Sing et al, 2002). The cell receptors responsible for LcrV-induced IL-10 production were identified as CD14 and TLR2 (Sing et al, 2002).…”

“…IL-10 secretion in response to rLcrV was abrogated in CD14-and TLR2-deficient m a cr o ph ag e s . Fu r th erm o r e , th e T L R 2 s t imu l a t ing r eg i on o f L c r V m app e d t o a s h o rt Nterminal 19 amino acid sequence (Sing et al, 2002). CD14 / TLR2 mediated production of IL-10 by LcrV was further established by the observation that TLR2-deficient mice were more resistant to Y. enterocolitica infection than their wild-type parents (Sing et al, 2002).…”

“…It forms the tip of TTSS and helps to translocate effector proteins to host cells. LcrV can also be secreted into the environment (Fields et al, 1999) where it has been shown to down regulate host protective immune responses in an IL-10 mediated manner (Sing et al, 2002). Thus, pretreatment of wildtype peritoneal macrophages with recombinant LcrV (rLcrV) inhibited zymosan induced TNF-production.…”

“…LcrV, is an important virulence factor (Sing et al, 2002;Fields et al, 1999;Lee et al, 2000). It forms the tip of TTSS and helps to translocate effector proteins to host cells.…”