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Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis.

Fehr T, Schoedon G, Odermatt B, Holtschke T, Schneemann M, Bachmann MF, Mak TW, Horak I, Zinkernagel RM - J. Exp. Med. (1997)

Bottom Line: However, the involved signaling pathways and effector mechanisms are still poorly understood.This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal.These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Immunology, University Hospital, Zürich, Switzerland.

ABSTRACT
Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF) 1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP-/- and to a lesser degree also IRF2-/- mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

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Proposed possible  signaling events in macrophages after Listeria infection. IFN-γ–induced  ICSBP is of crucial importance  for protection in murine listeriosis,  probably partly via ROI production. G-CSF (66) plays a minor  and IRF1-induced RNI (23) no  limiting role for bacterial resistance. A potentiating effect or an  additional factor is postulated.  How ICSBP, NF-IL6 or other  transcription factors are involved  in TNF-mediated protection  against Listeria remains to be determined.
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Figure 6: Proposed possible signaling events in macrophages after Listeria infection. IFN-γ–induced ICSBP is of crucial importance for protection in murine listeriosis, probably partly via ROI production. G-CSF (66) plays a minor and IRF1-induced RNI (23) no limiting role for bacterial resistance. A potentiating effect or an additional factor is postulated. How ICSBP, NF-IL6 or other transcription factors are involved in TNF-mediated protection against Listeria remains to be determined.

Mentions: From our findings in three different mouse strains and from the published literature, the following model of signaling events in activation of anti-Listeria immunity may be proposed (Fig. 6): after activation of IFN receptors various tyrosine kinases are induced and STAT proteins phosphorylated (Table 1); they regulate the induction and activation of transcription factors of the IRF family among which the exclusively IFN-γ-dependent ICSBP mediates protection against Listeria. Two major questions remain open: (a) What molecules are involved in the signalling of the TNF receptor that could explain its importance for anti-Listeria immunity (ICSBP, NF-IL6, other transcription factors, indirect effect via NK cell activation)? (b) How do macrophages kill Listeria? Our results, but also the published ones on IFN type II receptor- and iNOS-deficient mice, rather argue against RNI production being a limiting factor. ROI may be involved since ICSBP- and NF-IL6–deficient mice had reduced respiratory burst, and this correlated with high susceptibility to Listeria infection. But still there may be a potential third mechanism involved to explain the drastic phenotype of ICSBP−/− mice. Studies on iron metabolism of peritoneal macrophages (64) and murine β-thalassemia (65) suggested that iron scavengers lead to enhanced, and iron overload to reduced, resistance to Listeria by direct interference with the essential bacterial iron metabolism. Whether IFN-γ– and/or TNF-α–mediated enhancement of iron-binding proteins can explain resistance to murine listeriosis remains to be investigated.


Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis.

Fehr T, Schoedon G, Odermatt B, Holtschke T, Schneemann M, Bachmann MF, Mak TW, Horak I, Zinkernagel RM - J. Exp. Med. (1997)

Proposed possible  signaling events in macrophages after Listeria infection. IFN-γ–induced  ICSBP is of crucial importance  for protection in murine listeriosis,  probably partly via ROI production. G-CSF (66) plays a minor  and IRF1-induced RNI (23) no  limiting role for bacterial resistance. A potentiating effect or an  additional factor is postulated.  How ICSBP, NF-IL6 or other  transcription factors are involved  in TNF-mediated protection  against Listeria remains to be determined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196174&req=5

Figure 6: Proposed possible signaling events in macrophages after Listeria infection. IFN-γ–induced ICSBP is of crucial importance for protection in murine listeriosis, probably partly via ROI production. G-CSF (66) plays a minor and IRF1-induced RNI (23) no limiting role for bacterial resistance. A potentiating effect or an additional factor is postulated. How ICSBP, NF-IL6 or other transcription factors are involved in TNF-mediated protection against Listeria remains to be determined.
Mentions: From our findings in three different mouse strains and from the published literature, the following model of signaling events in activation of anti-Listeria immunity may be proposed (Fig. 6): after activation of IFN receptors various tyrosine kinases are induced and STAT proteins phosphorylated (Table 1); they regulate the induction and activation of transcription factors of the IRF family among which the exclusively IFN-γ-dependent ICSBP mediates protection against Listeria. Two major questions remain open: (a) What molecules are involved in the signalling of the TNF receptor that could explain its importance for anti-Listeria immunity (ICSBP, NF-IL6, other transcription factors, indirect effect via NK cell activation)? (b) How do macrophages kill Listeria? Our results, but also the published ones on IFN type II receptor- and iNOS-deficient mice, rather argue against RNI production being a limiting factor. ROI may be involved since ICSBP- and NF-IL6–deficient mice had reduced respiratory burst, and this correlated with high susceptibility to Listeria infection. But still there may be a potential third mechanism involved to explain the drastic phenotype of ICSBP−/− mice. Studies on iron metabolism of peritoneal macrophages (64) and murine β-thalassemia (65) suggested that iron scavengers lead to enhanced, and iron overload to reduced, resistance to Listeria by direct interference with the essential bacterial iron metabolism. Whether IFN-γ– and/or TNF-α–mediated enhancement of iron-binding proteins can explain resistance to murine listeriosis remains to be investigated.

Bottom Line: However, the involved signaling pathways and effector mechanisms are still poorly understood.This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal.These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Immunology, University Hospital, Zürich, Switzerland.

ABSTRACT
Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF) 1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP-/- and to a lesser degree also IRF2-/- mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-gamma in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-gamma stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-gamma-mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

Show MeSH
Related in: MedlinePlus