Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

Suh, Hyeon Sook; Zhao, Meng; Rivieccio, Mark A.; Choi, Shinyeop; Connolly, Erin C.; Zhao, Yongmei; Takikawa, Osamu; Brosnan, Celia F.; Lee, Sunhee C.

doi:10.1128/jvi.00792-07

Cited by 88 publications

(105 citation statements)

References 87 publications

(113 reference statements)

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“…42 Irrespective of whether IDO itself may contribute to the antimicrobial innate function of ECs, our data indicate an important role for the MyD88 pathway in ECs in the control of fungal growth, a finding suggesting the possible antifungal effector activity of ECs. In this regard, despite the fact that airways ECs phagocytose Aspergillus conidia, 16,17 the ability of conidia to survive in ECs 17 was taken to indicate airways ECs as a possible fungus reservoir.…”

Section: Discussionmentioning

confidence: 82%

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

et al. 2010

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Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established, we determined that epithelial cells (ECs) also contributes to this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase (IDO) via non-canonical nuclear factor-kB activation. Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis, bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice, underexpressed the IDO-dependent T helper 1/regulatory T cell (Th1/Treg) pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs. Further studies with interferon (IFN)-c, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-c/IDO/ Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth. Thus, distinct immune pathways contribute to resistance and tolerance to the fungus, to which the hematopoietic/non-hematopoietic compartments contribute through distinct, yet complementary, roles.

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Section: Discussionmentioning

confidence: 82%

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

et al. 2010

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“…39 For astrocytes, three different combinations of stimuli were applied (IL-1␤ alone, IL-1 and IFN-␥, or PIC) based on previously determined gene expression patterns. 22,27,34 Human astrocytes respond minimally to LPS; therefore, we excluded this stimulus for astrocytes. 40 A pilot experiment for dose response showed that 3-HAA at 100 mol/L maximally inhibited IFN-␥ inducible protein 10 (IP-10) production in astrocytes (Figure 2A), and thus all subsequent experiments were performed using 100 mol/L 3-HAA.…”

Section: -Haa Suppresses Cytokine and Chemokine Productionmentioning

confidence: 99%

“…The blots were blocked in Tris-buffered saline and 0.1% Tween-20 containing 5% nonfat milk and then incubated with antibodies at 4°C for 16 hours. 34 34 The secondary antibody was either horseradish peroxidase-conjugated anti-mouse or anti-rabbit IgG (Pierce Biotechnology, Rockford, IL) and was used at 1:2000 to 1:10,000 for 1 hour at room temperature. Signals were developed using enhanced chemiluminescence (Pierce Biotechnology).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…34 Briefly, cell cultures in 60-mm dishes were scraped into lysis buffer [10 mmol/L Tris-HCl (pH 8.8), 50 mmol/L NaCl, 0.5 mmol/L Na 3 VO 4 , 30 mmol/L Na 4 P 2 O 7 , 50 mmol/L NaF, 2 mmol/L EDTA, and 1% Triton X-100] at various time points. Thirty to 70 g of protein was separated by 10% SDS-PAGE and then transferred to polyvinylidene difluoride membrane.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Quantitative real-time RT-PCR was performed as described previously, 34,35 using porphobilinogen deaminase (PBDA; cell culture) or ␤-actin (mouse brain tissue) as an internal control. Primer sequences for human HO-1 were as follows: forward: 5=-ATGACACCAAGGACCA-GAGC-3= and reverse: 5=-GTGTAAGGACCCATCG-GAGA-3=.…”

Section: Real-time Pcrmentioning

confidence: 99%

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The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

Krause

Suh

Tarassishin

et al. 2011

The American Journal of Pathology

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136

104

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Tryptophan metabolism by the kynurenine pathway (KP) is important to the pathogenesis of inflammatory, infectious, and degenerative diseases. The 3-hydroxykynurenine (3-HK) branch of the KP is activated in macrophages and microglia, leading to the generation of 3-HK, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid, which are considered neurotoxic owing to their free radical-generating and N-methyl-D-aspartic acid receptor agonist activities. We investigated the role of 3-HAA in inflammatory and antioxidant gene expression and neurotoxicity in primary human fetal central nervous system cultures treated with cytokines (IL-1 with or without interferon-␥) or with Toll-like receptor ligands mimicking the proinflammatory central nervous system environment. Results were analyzed by microarray, Western blot, immunostain, enzyme-linked immunosorbent assay, and neurotoxicity assays. 3-HAA suppressed glial cytokine and chemokine expression and reduced cytokine-induced neuronal death. 3-HK also suppressed cytokineinduced neuronal death. Unexpectedly, 3-HAA was highly effective in inducing in astrocytes the expression of hemeoxygenase-1 (HO-1), an antioxidant enzyme with anti-inflammatory and cytoprotective properties. Indoleamine-2,3-dioxygenase (IDO) is an interferon (IFN)-␥-inducible, rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan metabolism generating various downstream metabolites collectively termed "kynurenines" 1 ( Figure 1). This process is compartmentalized due to cell-specific expression of the KP enzymes. For example, kynurenine monooxygenase (KMO) is expressed in macrophages and microglia, 2-4 whereas kynurenine aminotransferase II (KAT II) is present in astrocytes.5 A well-appreciated biological activity of IDO is T-cell suppression. IDO expressed in antigen-presenting cells (dendritic cells, macrophages, and microglia) can

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Indoleamine 2,3‐Dioxygenase: Transcriptional Regulation and Autoimmunity

Belladonna

Orabona

Volpi

et al. 2009

The Epigenetics of Autoimmune Diseases

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Indoleamine 2,3-dioxygenase (IDO) is a haem-containing enzyme that catalyses the oxidative cleavage of the indole ring in L-tryptophan (L-Trp), regulating this amino acid catabolism at the initial, rate-limiting level in a specific pathway. L-Trp, the least abundant of the essential amino acids, is utilized for protein synthesis and as a precursor of the neurotransmitter serotonin, yet the majority of the dietary intake is degraded along the so-called kynurenine pathway (named after the first metabolite, L-kynurenine), eventually leading to the biosynthesis of NAD þ . However, the same metabolic pathway, with initial formation of L-kynurenine, can be activated by two distinct, poorly homologous (12%) enzymes: IDO and tryptophan 2,3-dioxygenase (TDO).TDO is a constitutive enzyme restricted to the liver, whereas IDO is an inducible, intracellular enzyme widely expressed in several organs, and in particular in the lung, small and large intestine, spleen, kidney, stomach, brain and placenta. Remarkable expression of IDO is found in myeloid lineage cells (dendritic cells (DCs), monocytes, macrophages, eosinophils), epithelial cells, fibroblasts, vascular smooth muscle and endothelial cells, and in certain tumours as well. The two enzymes differ in substrate specificity. TDO is highly specific for the L-isomer of Trp, whereas IDO is capable of oxidizing a broad range of substrates, including not only L-Trp, but also D-Trp,

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Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

Cited by 88 publications

References 87 publications

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

Indoleamine 2,3‐Dioxygenase: Transcriptional Regulation and Autoimmunity

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