Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism
2017
Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is critical for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other. Melatonin, the end product of the serotonin pathway, played an important role in tryptophan metabolism by affecting both key enzymes of the two pathways. Melatonin treatment induced the expression of IDO1 and enhanced the activity of IDO1 promoter while decreasing the expression of AANAT. Melatonin treatment up-regulated the expression of FoxO1 and enhanced the binding of FoxO1 to the IDO1 promoter. FoxO1 was clarified to be a new regulator for IDO1 expression. Melatonin treatment decreased the phosphorylation of FoxO1 by ERK1/2 and AKT and increased the phosphorylation of binding protein 14-3-3 by JNK, thus the complex of FoxO1/14-3-3 in the cytoplasm was disassembled and FoxO1 was relocated to the nucleus to induce IDO1 expression. The JNK signaling pathway played an important role in melatonin induced IDO1 up-regulation. In conclusion, this study suggests a link between melatonin/JNK/FoxO1/IDO1 to be a potential balance regulator of tryptophan metabolism, and offers a new approach to treat diseases related to dysregulation of tryptophan metabolism.
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