Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.

Exhaled breath condensate formate after inhaled allergen provocation in atopic asthmatics in vivo.

OBJECTIVE: The dual actions of S-nitrosoglutathione reductase comprise reduction of S-nitrosoglutathione, a potent endogenous airway smooth muscle relaxant that is depleted in asthmatics, and detoxification of formaldehyde to formate. Airway formate production is increased in children with asthma, suggesting increased activity of S-nitrosoglutathione reductase. We determined formate in exhaled breath condensate from adult atopic asthmatics with asthma exacerbation produced by inhaled allergen in vivo, METHODS: Twenty-two adult atopic asthmatics underwent inhaled allergen challenge using specific allergen. Exhaled breath condensate was collected at baseline, 1 h after inhalation of the provocative dose of allergen, and then every 2 h for 8 h during the challenge. Formate was analyzed by ion chromatography, RESULTS: Eleven asthmatics developed an isolated early airway response, and another 11 volunteers early response followed by late airway response (dual response). Formate concentrations doubled 1 h post-challenge in asthmatics with dual-airway response but essentially unchanged in patients with an isolated early reaction, CONCLUSIONS: Dual-airway response to allergen in atopic asthmatics could be associated with increased activity of S-nitrosoglutathione reductase as suggested by greater concentrations of formate in exhaled breath condensate. Measurement of formate in exhaled breath condensate could serve as a noninvasive biomarker of S-nitrosoglutathione reductase activity in vivo. Our results need to be confirmed in a larger group of asthmatics.

Specialized role for a murine class I-b MHC molecule in prokaryotic host defenses.

Although nonclassical (class I-b) gene products represent the majority of murine major histocompatibility complex (MHC) genes, the role of these relatively nonpolymorphic molecules remains uncertain. Recently, one such protein, H-2M3 (formerly designated Hmt), was shown to bind and specifically present N-formylated peptides to cytotoxic T lymphocytes. Because N-formylation is characteristic of prokaryotic proteins, this MHC molecule may be especially adapted for a role in the mammalian defense against bacterial attack. The current studies demonstrate that an MHC molecule, indistinguishable from H-2M3, presents antigens derived from the intracellular pathogen Listeria monocytogenes to Listeria-specific CD8+ cells.