A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium

Abstract

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

Figure 1

The kynurenine pathway of tryptophan metabolism, with enzymes and cofactors involved. Dashed arrow shafts indicate reactions with more than one step: Black arrows pointing up-wards indicate the enzymes which are stimulated by IFN-γ. AA: anthranilic acid; ACMS: α-amino-β-carboxymuconate-ε-semialdehyde; ACMSD: α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase; AMS: α-aminomuconate-ε-semialdehyde; B2: vitamin B2 (flavin adenine dinucleotide); B6: vitamin B6 (pyridoxal 5′-phosphate, PLP); HAA: 3-hydroxyanthranilic acid; HAAO: 3-Hydroxyanthranilate 3,4-dioxygenase; HK: 3-hydroxykynurenine; IDO: indoleamine (2,3)-dioxygenase; KA: kynurenic acid; KAT: kynurenine aminotransferase; KMO: kynurenine 3-monooxygenase; KYNU: kynureninase; NAD: nicotine adenine dinucleotide; TDO: tryptophan (2,3)-dioxygenase; PIC: picolinic acid; QA: quinolinic acid; QPRT: quinolinate phosphoribosyltransferase; XA: xanthurenic acid.

Figure 2

Qgraph plot of spearman correlations (including only absolute values > 0.2 to avoid a crowded figure) adjusted for cohort, sex, age, BMI, creatinine, cotinine and sample storage time. Green lines show positive correlations, red lines show inverse correlations. The color saturation and thickness of lines are proportional to the strength of the correlations. The figure illustrates the data given in Supplementary Table S2. AA: anthranilic acid; CRP: C-reactive protein; HAA: 3-hydroxyanthranilic acid; HK: 3-hydroxykynurenine; KA: kynurenic acid; KTR: kynurenine/tryptophan ratio; Kyn: kynurenine; Neo: neopterin; PLP: pyridoxal 5′-phosphate; Rf: riboflavin; Trp: tryptophan; QA: quinolinic acid; XA: xanthurenic acid.

Figure 3

Relative importance of predictors of kynurenines. The percentage of variance of tryptophan and kynurenines explained by regression models using relaimpo. All continuous variables were log-transformed and then centered on the mean and standardized by dividing by the standard deviation. Black bars are used for predictors that showed positive regression coefficients in the mixed models (Table 2), those with negative coefficients are shown in grey. KTR and neopterin were included in separate models, and the models were adjusted for cohorts. AA: anthranilic acid; BMI: body mass index; CRP: C-reactive protein; HAA: 3-hydroxyanthranilic acid; HK: 3-hydroxykynurenine; KA: kynurenic acid; KTR: kynurenine/tryptophan ratio; PLP: pyridoxal 5′-phosphate; QA: quinolinic acid; XA: xanthurenic acid.