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Review
. 2015:2015:973548.
doi: 10.1155/2015/973548. Epub 2015 Dec 31.

Endotoxin-Induced Tryptophan Degradation along the Kynurenine Pathway: The Role of Indolamine 2,3-Dioxygenase and Aryl Hydrocarbon Receptor-Mediated Immunosuppressive Effects in Endotoxin Tolerance and Cancer and Its Implications for Immunoparalysis

Elisa Wirthgen  1 , Andreas Hoeflich  1
Affiliations
Review

Endotoxin-Induced Tryptophan Degradation along the Kynurenine Pathway: The Role of Indolamine 2,3-Dioxygenase and Aryl Hydrocarbon Receptor-Mediated Immunosuppressive Effects in Endotoxin Tolerance and Cancer and Its Implications for Immunoparalysis

Elisa Wirthgen et al. J Amino Acids. 2015.

Abstract

The degradation of tryptophan (TRP) along the kynurenine pathway plays a crucial role as a neuro- and immunomodulatory mechanism in response to inflammatory stimuli, such as lipopolysaccharides (LPS). In endotoxemia or sepsis, an enhanced activation of the rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO) is associated with a higher mortality risk. It is assumed that IDO induced immunosuppressive effects provoke the development of a protracted compensatory hypoinflammatory phase up to a complete paralysis of the immune system, which is characterized by an endotoxin tolerance. However, the role of IDO activation in the development of life-threatening immunoparalysis is still poorly understood. Recent reports described the impact of inflammatory IDO activation and aryl hydrocarbon receptor- (AhR-) mediated pathways on the development of LPS tolerance and immune escape of cancer cells. These immunosuppressive mechanisms offer new insights for a better understanding of the development of cellular dysfunctions in immunoparalysis. This review provides a comprehensive update of significant biological functions of TRP metabolites along the kynurenine pathway and the complex regulation of LPS-induced IDO activation. In addition, the review focuses on the role of IDO-AhR-mediated immunosuppressive pathways in endotoxin tolerance and carcinogenesis revealing the significance of enhanced IDO activity for the establishment of life-threatening immunoparalysis in sepsis.

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Figures

Figure 1
Figure 1
Main pathways of TRP degradation including enzymes and their potential stimuli (modified after [1, 4, 16, 35]). Superscripted numbers indicate described biological effects of TRP metabolites. Black arrows mark enzymatic reactions and dashed arrows include more than one catalytic reaction step. Enzymes: FOR = formamidase, IDO = indolamine 2,3-dioxygenase; TDO = tryptophan 2,3-dioxygenase, TPH = tryptophan hydroxylase; KAT = kynurenine aminotransferase, KMO = kynurenine 3-monooxygenase; KYNU = kynureninase, HADO = 3-hydroxyanthranilic acid dioxygenase; HAAO = 3-hydroxyanthranilic acid oxidase, AMO = anthranilate 3-monooxygenase, and AADC = aromatic L-amino acid decarboxylase; AANAT = N-acetyltransferase; HIOMT = hydroxy-O-methyltransferase.
Figure 2
Figure 2
Schematic illustration of an inflammatory IDO activation by LPS and inflammatory cytokines and possible regulatory mechanisms on transcriptional, posttranscriptional, and posttranslational level.
Figure 3
Figure 3
Schematic illustration of possible interaction between inflammatory IDO activation and AhR-mediated effects. IDO1 plays a crucial role in the generation of LPS-induced endotoxin tolerance whereas combined effects of AhR, IDO1, and TGF-β are required. L-kynurenine alone failed to restore tolerance in the absence of IDO1 indicating nonenzymatic functions as intracellular signaling. It was found that IDO1 specific phosphorylation by AhR triggered kinase activity induces reprograming of gene expression leading to TGF-β in response to TLR signaling. Studies on human cancer cells showed that IDO induced KYN activates the AhR-ARNT associated transcription of IL-6 which promotes autocrine activation of IDO1 via STAT3 supporting the theory that IDO-mediated immunosuppression enables effectively immune escape of tumor cells.
Figure 4
Figure 4
Enhanced IDO activity and its indicators as potential risk factors for the development of immunoparalysis and poor prognosis in sepsis. Patients with poor outcome have enhanced IDO activity in early state of sepsis leading to increased levels of KYN and KYNA that provokes expression of TGF-β, IL-6, and development of endotoxin tolerance. In ongoing sepsis, IL-6 does not decrease significantly in plasma of nonsurvivors enabling the autocrine activation of IDO via AhR-IL-6-STAT3 loop. The enhanced IDO activity mediates immunosuppressive effects as increased generation of Tregs in ongoing sepsis, provoking the establishment of immunoparalysis.
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