The tryptophan metabolite picolinic acid suppresses proliferation and metabolic activity of CD4+ T cells and inhibits c-Myc activation

Abstract

Tryptophan metabolites, including kynurenine, 3-hydroxyanthranilic acid, and picolinic acid, are key mediators of immunosuppression by cells expressing the tryptophan-catabolizing enzyme indoleamine2,3-dioxygenase. In this study, we assessed the influence of picolinic acid on cell viability and effector functions of CD4(+)T cells following in vitro activation with agonistic anti-CD3/anti-CD28 antibodies. In contrast to kynurenine and 3-hydroxyanthranilic acid, exposure of T cells with picolinic acid did not affect cell viability, whereas proliferation and metabolic activity were suppressed in a dose-dependent manner. On the other hand, cytokine secretion and up-regulation of cell surface activation markers were not or only weakly inhibited by picolinic acid. Picolinic acid exposure induced a state of deep anergy that could not be overcome by the addition of exogenous IL-2 and inhibited Th cell polarization. On the molecular level, important upstream signaling molecules, such as the MAPKs ERK and p38 and the mammalian target of rapamycin target protein S6 ribosomal protein, were not affected by picolinic acid. Likewise, NFAT, NF-κB, and AP-1 promoter activity in Jurkat T cells was not influenced by exposure to picolinic acid. Whereas transcriptional levels of v-myc avian myelocytomatosis viral oncogene homolog were not affected by picolinic acid, phosphorylation at Ser62 was strongly reduced in picolinic acid-exposed T cells following activation. In conclusion, picolinic acid mediates a unique immunosuppressive program in T cells, mainly inhibiting cell cycle and metabolic activity, while leaving other effector functions intact. These functional features are accompanied by reduced phosphorylation of v-myc avian myelocytomatosis viral oncogene homolog. It remains to be determined whether this effect is mediated by direct inhibition of ERK activity or whether indirect mechanisms apply.

Metabolite Profile Differences Among Different Storage Time in Beef Preserved at Low Temperature

“…Xanthine is the precursor of urocanic acid and is generated from hypoxanthine and guanine (Meeliset et al., ; Wu, Jia, & Dong, ), which were also accumulated in displayed meat. In addition, there is evidence showing the influence of picolinic acid in suppressing the proliferation and metabolic activity of T‐cell and thus mediating immunosuppression in T‐cell (Prodinger et al., ). Although this data was derived from in vitro studies with higher picolinic acid concentration than the content in body, it give us implications of the increased toxicity potential in beef meat during storage at 4 °C for more than 3.5 days.…”

Prospective study of blood metabolites associated with colorectal cancer risk

“…22 It may mediate immunosuppression by inhibiting proliferation and metabolic activity of CD4+ T cells. 23 On the other hand, picolinic acid has also been reported to have an anti-tumor effect, with a reduced tumor cell proliferation found in an animal study administered with picolinic acid. 24 More research on this metabolite is needed.…”

The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy

“…Quinolinic acid stimulates the cell cycle of cancer cells and contributes to the acquisition of multidrug resistance against chemotherapeutic agents ( 29 ). Picolinic acid inhibits effector T cell proliferation ( 31 ). Later, it has become clear that the balance between the immunoprotective and immunosuppressive roles of IDO1 and Trp metabolites is tightly controlled by the stoichiometry of available local factors (e.g., IL-6, IL-12, CD40, IFN-γ, CTLA4, Foxo3a, IL-10, and PD-1) ( 26 , 32 ).…”