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Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

Jones SP, Franco NF, Varney B, Sundaram G, Brown DA, de Bie J, Lim CK, Guillemin GJ, Brew BJ - PLoS ONE (2015)

Bottom Line: In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma.Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin.Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells.

View Article: PubMed Central - PubMed

Affiliation: Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, Australia.

ABSTRACT
The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.

No MeSH data available.


Related in: MedlinePlus

Correlations of IDO-1, KMO and QPRT expression (gMFI) with KYN:TRP ratio, QUIN concentration (nM) and neopterin levels (nM).Data was log10 transformed to normalize distributions. Straight-line fits show least squares regression with the r2 value providing a summary of fit. P values were computed using ANOVA for a regression analysis of the total variation for each correlation (n = 24).
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pone.0131389.g005: Correlations of IDO-1, KMO and QPRT expression (gMFI) with KYN:TRP ratio, QUIN concentration (nM) and neopterin levels (nM).Data was log10 transformed to normalize distributions. Straight-line fits show least squares regression with the r2 value providing a summary of fit. P values were computed using ANOVA for a regression analysis of the total variation for each correlation (n = 24).

Mentions: We found significant correlations between the expression of IDO-1, KMO and QPRT with KYN:TRP ratio, QUIN concentration and neopterin levels (Fig 5). We also observed a significant correlation between 3-HK and QPRT (r2 = 0.2746, p = 0.0086, data not shown).


Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

Jones SP, Franco NF, Varney B, Sundaram G, Brown DA, de Bie J, Lim CK, Guillemin GJ, Brew BJ - PLoS ONE (2015)

Correlations of IDO-1, KMO and QPRT expression (gMFI) with KYN:TRP ratio, QUIN concentration (nM) and neopterin levels (nM).Data was log10 transformed to normalize distributions. Straight-line fits show least squares regression with the r2 value providing a summary of fit. P values were computed using ANOVA for a regression analysis of the total variation for each correlation (n = 24).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482723&req=5

pone.0131389.g005: Correlations of IDO-1, KMO and QPRT expression (gMFI) with KYN:TRP ratio, QUIN concentration (nM) and neopterin levels (nM).Data was log10 transformed to normalize distributions. Straight-line fits show least squares regression with the r2 value providing a summary of fit. P values were computed using ANOVA for a regression analysis of the total variation for each correlation (n = 24).
Mentions: We found significant correlations between the expression of IDO-1, KMO and QPRT with KYN:TRP ratio, QUIN concentration and neopterin levels (Fig 5). We also observed a significant correlation between 3-HK and QPRT (r2 = 0.2746, p = 0.0086, data not shown).

Bottom Line: In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma.Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin.Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells.

View Article: PubMed Central - PubMed

Affiliation: Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, Australia.

ABSTRACT
The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.

No MeSH data available.


Related in: MedlinePlus