Tryptophan Metabolism Along the Kynurenine Pathway Downstream of Toll-like Receptor Stimulation in Peripheral Monocytes.
Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representing the first line of immune defence against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of this study was to investigate whether stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan. Stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8 and TLR-9 was found to induce the production of kynurenine, but only stimulation of TLR-3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TLR-1, TLR-5 and TLR-6 did not induce the kynurenine pathway. Taken together, this study provides novel evidence demonstrating that TLR activation induces a pattern of downstream tryptophan degradation along the kynurenine pathway in monocytes. The results of this study may implicate that TLRs can be used as new drug targets for the regulation of aberrant tryptophan metabolism along this pathway, a potential therapeutic strategy that may be of importance in several disorders.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Orhan
Protein Biomarkers, Personalized Healthcare & Biomarker Laboratories, Innovative Medicines, Gothenburg, Sweden.
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Bhat
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Department of Medicinal Chemistry, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.
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Sandberg
Protein Biomarkers, Personalized Healthcare & Biomarker Laboratories, Innovative Medicines, Gothenburg, Sweden.|Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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Ståhl
Department of Clinical Neuroscience Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
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Piehl
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Svensson
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Erhardt
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. lilly.schwieler@ki.se.
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Schwieler
D005408:Flagellin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D006868:Hydrolysis; D007093:Imidazoles / Q000494:pharmacology; D007736:Kynurenic Acid / Q000276:immunology / Q000378:metabolism; D007737:Kynurenine / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000737:chemistry; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000276:immunology; D017378:Quinolinic Acid / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D014364:Tryptophan / Q000276:immunology* / Q000378:metabolism
D007093:Imidazoles; D055666:Lipopeptides; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D051193:Toll-Like Receptors; D005408:Flagellin; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D011070:Poly I-C; C402365:resiquimod