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

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.