Indoleamine 2,3-dioxygenase–expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection
Alexey Popov, … , Olaf Utermöhlen, Joachim L. Schultze
Alexey Popov, … , Olaf Utermöhlen, Joachim L. Schultze
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3160-3170. https://doi.org/10.1172/JCI28996.
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Research Article Immunology

Indoleamine 2,3-dioxygenase–expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection

Abstract

Control of pathogens by formation of abscesses and granulomas is a major strategy of the innate immune system, especially when effector mechanisms of adaptive immunity are insufficient. We show in human listeriosis that DCs expressing indoleamine 2,3-dioxygenase (IDO), together with macrophages, are major cellular components of suppurative granulomas in vivo. Induction of IDO by DCs is a cell-autonomous response to Listeria monocytogenes infection and was also observed in other granulomatous infections with intracellular bacteria, such as Bartonella henselae. Reporting on our use of the clinically applied anti–TNF-α antibody infliximab, we further demonstrate in vitro that IDO induction is TNF-α dependent. Repression of IDO therefore might result in exacerbation of granulomatous diseases observed during anti–TNF-α therapy. These findings place IDO+ DCs not only at the intersection of innate and adaptive immunity but also at the forefront of bacterial containment in granulomatous infections.

Authors

Alexey Popov, Zeinab Abdullah, Claudia Wickenhauser, Tomo Saric, Julia Driesen, Franz-Georg Hanisch, Eugen Domann, Emma Lloyd Raven, Oliver Dehus, Corinna Hermann, Daniela Eggle, Svenja Debey, Trinad Chakraborty, Martin Krönke, Olaf Utermöhlen, Joachim L. Schultze

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Figure 5

Neutralization of TNF-α or IFN-γ during L. monocytogenes infection downregulates IDO expression and enzymatic activity.

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Neutralization of TNF-α or IFN-γ during L. monocytogenes infection downr...
immDCs were infected for 30 minutes at MOI 5, washed, and subsequently cultured for 24 hours in the absence or presence of neutralizing TNF-α antibody (infliximab, 0.1–10 μg/ml), anti–IFN-γ antibody (1 μg/ml), anti–IFN-β (1 μg/ml) or COX-2 inhibitor (rofecoxib, 1 μM). (A) IDO mRNA expression was assessed by quantitative real-time PCR. B2M was used as a housekeeping gene control; IDO expression of differentially treated DCs was normalized to the expression of infected, untreated DCs derived from the same donor. Mean ± SD of at least 3 experiments per condition are shown. Asterisks highlight statistically significant comparisons (*P < 0.05, **P < 0.005, ***P < 0.0005). (B) Protein expression of IDO was assessed by immunoblotting; rhIDO was used as a positive control. Data shown are derived from 1 representative experiment out of 3. (C) Kynurenine accumulation in the same cultures was assessed using a photometric assay. Shown here are mean ± SD of at least 3 independent experiments. Legend underneath C also applies to A and B. Asterisks highlight statistically significant comparisons (*P < 0.05, #P < 0.01). Detection of IFN-γ (D) and TNF-α (E) in supernatants from the same cultures described above. Shown here are mean ± SD derived from at least 2 donors. Asterisks highlight statistically significant comparisons (*P < 0.05, ##P < 0.0001).