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The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects.

Müller A, Heseler K, Schmidt SK, Spekker K, Mackenzie CR, Däubener W - J. Cell. Mol. Med. (2009)

Bottom Line: The interferon (IFN)-gamma-inducible tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties.Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence.We found that the minimum concentration of tryptophan required for bacterial growth is 10-40-fold higher than the minimum concentration necessary for T-cell activation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-Universität Düsseldorf, Germany.

ABSTRACT
The interferon (IFN)-gamma-inducible tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties. In this study, we provide evidence that both tryptophan starvation and production of toxic tryptophan metabolites are involved in the immunoregulation mediated by IDO, whereas tryptophan starvation seems to be the only antibacterial effector mechanism. A long-studied controversy in the IDO research field is the seemingly contradictory effect of IDO in the defence against infectious diseases. On the one hand, IFN-gamma-induced IDO activity mediates an antimicrobial effect, while at the same time IDO inhibits T-cell proliferation and IFN-gamma production. Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence. We found that the minimum concentration of tryptophan required for bacterial growth is 10-40-fold higher than the minimum concentration necessary for T-cell activation. Therefore, we suggest that during the first phase of infection the IDO-mediated tryptophan depletion has a predominantly antimicrobial effect whereas in the next stage, and with ongoing tryptophan degradation, the minimum threshold concentration of tryptophan for T-cell activation is undercut, resulting in an inhibition of T-cell growth and subsequent IDO activation.

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Different effects of kynurenine on the proliferation of T cells and bacteria. Staphylococcal growth in presence of different concentrations of kynurenine was analysed photometrically (A). Anti-CD3-driven T-cell activation was analysed in absence or presence of different concentrations of kynurenine (B). In both experiments, a part of the cultures was supplemented with tryptophan (100 μg/ml). Data are given as mean ± S.E.M. of three independent experiments, each done in triplicate.
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fig05: Different effects of kynurenine on the proliferation of T cells and bacteria. Staphylococcal growth in presence of different concentrations of kynurenine was analysed photometrically (A). Anti-CD3-driven T-cell activation was analysed in absence or presence of different concentrations of kynurenine (B). In both experiments, a part of the cultures was supplemented with tryptophan (100 μg/ml). Data are given as mean ± S.E.M. of three independent experiments, each done in triplicate.

Mentions: Having shown that the supernatant of IFN-γ stimulated cells was depleted of tryptophan, this conditioned medium was used to analyse bacterial growth. As indicated in Fig. 4B, we found that, independent of the amount of tryptophan initially added to the cultures, a strong antibacterial effect could be detected. To show that the lack of bacterial growth in the cell culture supernatants is due to IDO-induction and subsequent tryptophan degradation, we added large amounts of tryptophan (100 μg/ml) to the supernatants at the time of infection. As also shown in Fig. 4B, this results in a complete restoration of bacterial growth, indicating that the kynurenine concentration present in the cultures did not influence bacterial growth. This was also supported by the finding that kynurenine, added in different amounts into bacterial cultures, did not influence bacterial growth (Fig. 5A).


The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects.

Müller A, Heseler K, Schmidt SK, Spekker K, Mackenzie CR, Däubener W - J. Cell. Mol. Med. (2009)

Different effects of kynurenine on the proliferation of T cells and bacteria. Staphylococcal growth in presence of different concentrations of kynurenine was analysed photometrically (A). Anti-CD3-driven T-cell activation was analysed in absence or presence of different concentrations of kynurenine (B). In both experiments, a part of the cultures was supplemented with tryptophan (100 μg/ml). Data are given as mean ± S.E.M. of three independent experiments, each done in triplicate.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4496108&req=5

fig05: Different effects of kynurenine on the proliferation of T cells and bacteria. Staphylococcal growth in presence of different concentrations of kynurenine was analysed photometrically (A). Anti-CD3-driven T-cell activation was analysed in absence or presence of different concentrations of kynurenine (B). In both experiments, a part of the cultures was supplemented with tryptophan (100 μg/ml). Data are given as mean ± S.E.M. of three independent experiments, each done in triplicate.
Mentions: Having shown that the supernatant of IFN-γ stimulated cells was depleted of tryptophan, this conditioned medium was used to analyse bacterial growth. As indicated in Fig. 4B, we found that, independent of the amount of tryptophan initially added to the cultures, a strong antibacterial effect could be detected. To show that the lack of bacterial growth in the cell culture supernatants is due to IDO-induction and subsequent tryptophan degradation, we added large amounts of tryptophan (100 μg/ml) to the supernatants at the time of infection. As also shown in Fig. 4B, this results in a complete restoration of bacterial growth, indicating that the kynurenine concentration present in the cultures did not influence bacterial growth. This was also supported by the finding that kynurenine, added in different amounts into bacterial cultures, did not influence bacterial growth (Fig. 5A).

Bottom Line: The interferon (IFN)-gamma-inducible tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties.Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence.We found that the minimum concentration of tryptophan required for bacterial growth is 10-40-fold higher than the minimum concentration necessary for T-cell activation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-Universität Düsseldorf, Germany.

ABSTRACT
The interferon (IFN)-gamma-inducible tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties. In this study, we provide evidence that both tryptophan starvation and production of toxic tryptophan metabolites are involved in the immunoregulation mediated by IDO, whereas tryptophan starvation seems to be the only antibacterial effector mechanism. A long-studied controversy in the IDO research field is the seemingly contradictory effect of IDO in the defence against infectious diseases. On the one hand, IFN-gamma-induced IDO activity mediates an antimicrobial effect, while at the same time IDO inhibits T-cell proliferation and IFN-gamma production. Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence. We found that the minimum concentration of tryptophan required for bacterial growth is 10-40-fold higher than the minimum concentration necessary for T-cell activation. Therefore, we suggest that during the first phase of infection the IDO-mediated tryptophan depletion has a predominantly antimicrobial effect whereas in the next stage, and with ongoing tryptophan degradation, the minimum threshold concentration of tryptophan for T-cell activation is undercut, resulting in an inhibition of T-cell growth and subsequent IDO activation.

Show MeSH
Related in: MedlinePlus