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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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Listeria titers in organs of different mouse strains deficient for  molecules in the IFN signaling pathway. (A) Mice deficient for IFN- related transcription factors (ICSBP, IRF1, IRF2; filled diamonds) or (B)  mice lacking functional IFN type I (A129; filled diamonds) or type II  (G129; filled circles) receptors and control littermates (open diamonds) were  infected with 5 × 103 CFU of Listeria intravenously. After 5 d bacterial titers were determined in liver and spleen. Groups of three to four mice  were analyzed. Each symbol represents one mouse. One representative  experiment of two is shown for each strain.
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Figure 1: Listeria titers in organs of different mouse strains deficient for molecules in the IFN signaling pathway. (A) Mice deficient for IFN- related transcription factors (ICSBP, IRF1, IRF2; filled diamonds) or (B) mice lacking functional IFN type I (A129; filled diamonds) or type II (G129; filled circles) receptors and control littermates (open diamonds) were infected with 5 × 103 CFU of Listeria intravenously. After 5 d bacterial titers were determined in liver and spleen. Groups of three to four mice were analyzed. Each symbol represents one mouse. One representative experiment of two is shown for each strain.

Mentions: Gene targeted mice deficient for ICSBP, IRF1, or IRF2 were infected with various doses of Listeria intravenously or peripherally i.f., and survival was monitored daily (Table 2). All ICSBP−/− mice died after injection of a dose as low as 50 CFU of Listeria, whereas five of six IRF2−/− mice succumbed to a dose of 5 × 103 CFU within 12 d. In contrast, IRF1−/− and wild-type mice resisted to a dose of 5 × 103 CFU injected intravenously. However, IRF1−/− mice on C57BL/6 background and held under strict SPF conditions also showed enhanced susceptibility to Listeria, when injected with a 5–10-times higher dose intraperitoneally (Ferrick, D., and H.W. Mittrücker, personal communication). Listeria titers in liver and spleen were determined 24 h after a high dose (2 × 105 CFU) and 5 d after an intermediate dose (5 × 103 CFU) of Listeria injected intravenously. In the first 24 h, when neutrophils seem to play an important role (2), there was almost no titer difference between the three strains and only a 10-fold difference compared to control mice (data not shown). However, after 5 d when activated macrophages are essential for control of Listeria infection, ICSBP−/− and IRF2−/− showed between 102- and 106-fold higher titers in liver and spleen, whereas IRF1−/− mice controlled Listeria replication comparable to controls (Fig. 1 A). In vitro gene regulation studies have revealed that ICSBP and IRF2 form complexes which then have a markedly enhanced DNA binding capacity to ISRE compared to the single factors (44). In contrast to IRF1, they are both negative regulators of classical IFN-induced genes. However, both transcription factors are obviously of major importance for early anti-Listeria immune responses. Since it has been shown that ICSBP−/− mice do not express IRF2 (although the gene is intact [36]), this can explain the even more drastic phenotype of ICSBP−/− compared to IRF2−/− mice, because they represent functionally a double knock-out phenotype.


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)

Listeria titers in organs of different mouse strains deficient for  molecules in the IFN signaling pathway. (A) Mice deficient for IFN- related transcription factors (ICSBP, IRF1, IRF2; filled diamonds) or (B)  mice lacking functional IFN type I (A129; filled diamonds) or type II  (G129; filled circles) receptors and control littermates (open diamonds) were  infected with 5 × 103 CFU of Listeria intravenously. After 5 d bacterial titers were determined in liver and spleen. Groups of three to four mice  were analyzed. Each symbol represents one mouse. One representative  experiment of two is shown for each strain.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Listeria titers in organs of different mouse strains deficient for molecules in the IFN signaling pathway. (A) Mice deficient for IFN- related transcription factors (ICSBP, IRF1, IRF2; filled diamonds) or (B) mice lacking functional IFN type I (A129; filled diamonds) or type II (G129; filled circles) receptors and control littermates (open diamonds) were infected with 5 × 103 CFU of Listeria intravenously. After 5 d bacterial titers were determined in liver and spleen. Groups of three to four mice were analyzed. Each symbol represents one mouse. One representative experiment of two is shown for each strain.
Mentions: Gene targeted mice deficient for ICSBP, IRF1, or IRF2 were infected with various doses of Listeria intravenously or peripherally i.f., and survival was monitored daily (Table 2). All ICSBP−/− mice died after injection of a dose as low as 50 CFU of Listeria, whereas five of six IRF2−/− mice succumbed to a dose of 5 × 103 CFU within 12 d. In contrast, IRF1−/− and wild-type mice resisted to a dose of 5 × 103 CFU injected intravenously. However, IRF1−/− mice on C57BL/6 background and held under strict SPF conditions also showed enhanced susceptibility to Listeria, when injected with a 5–10-times higher dose intraperitoneally (Ferrick, D., and H.W. Mittrücker, personal communication). Listeria titers in liver and spleen were determined 24 h after a high dose (2 × 105 CFU) and 5 d after an intermediate dose (5 × 103 CFU) of Listeria injected intravenously. In the first 24 h, when neutrophils seem to play an important role (2), there was almost no titer difference between the three strains and only a 10-fold difference compared to control mice (data not shown). However, after 5 d when activated macrophages are essential for control of Listeria infection, ICSBP−/− and IRF2−/− showed between 102- and 106-fold higher titers in liver and spleen, whereas IRF1−/− mice controlled Listeria replication comparable to controls (Fig. 1 A). In vitro gene regulation studies have revealed that ICSBP and IRF2 form complexes which then have a markedly enhanced DNA binding capacity to ISRE compared to the single factors (44). In contrast to IRF1, they are both negative regulators of classical IFN-induced genes. However, both transcription factors are obviously of major importance for early anti-Listeria immune responses. Since it has been shown that ICSBP−/− mice do not express IRF2 (although the gene is intact [36]), this can explain the even more drastic phenotype of ICSBP−/− compared to IRF2−/− mice, because they represent functionally a double knock-out phenotype.

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