Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages

Regan, T, Gill, AC ORCID: https://orcid.org/0000-0001-5201-9473, Clohisey, SM, Barnett, MW, Pariante, CM, Harrison, NA, Hume, DA, Bullmore, ET, Freeman, TC and MRC Immunopsychiatry Consortium, 2018. Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages. Journal of Leukocyte Biology, 103 (4), 681–692. ISSN 0741-5400

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Abstract

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression—notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.

Item Type:	Journal article
Publication Title:	Journal of Leukocyte Biology
Creators:	Regan, T., Gill, A.C., Clohisey, S.M., Barnett, M.W., Pariante, C.M., Harrison, N.A., Hume, D.A., Bullmore, E.T., Freeman, T.C. and MRC Immunopsychiatry Consortium
Publisher:	Society for Leukocyte Biology
Date:	April 2018
Volume:	103
Number:	4
ISSN:	0741-5400
Identifiers:	Number Type 10.1002/JLB.3A0617-261R DOI 2192353 Other
Rights:	This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Animal, Rural and Environmental Sciences
Record created by:	Jonathan Gallacher
Date Added:	15 Aug 2024 16:20
Last Modified:	15 Aug 2024 16:20
URI:	https://irep.ntu.ac.uk/id/eprint/52021

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