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

• DOI: 10.1002/jlb.3a0617-261r
• Publication Date: 2018-01-26T15:33:57Z
• Authors: Tim Regan; Andrew C Gill; Sara M Clohisey; Mark W Barnett; Carmine M Pariante; Neil A Harrison; David A Hume; Edward T Bullmore; Tom C Freeman
• Keywords: Monoaminergic; Indoleamine 2,3-dioxygenase; Kynurenine pathway

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