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

Several lines of evidence link macrophage activation and inflammation with nervous (monoaminergic) systems in the aetiology of depression. Interferon treatment is associated with depressive symptoms, whilst anti-TNF? therapies elicit positive mood. This study describes the actions of two monoaminergic antidepressants (escitalopram, nortriptyline) and three anti-inflammatory drugs (indomethacin, prednisolone, anti-TNF? antibody) on the response of human monocyte-derived macrophages (MDM) from six individuals to lipopolysaccharide or interferon-alpha. Expression profiling revealed robust changes in the MDM transcriptome (3,294 genes at P<0.001) following LPS challenge, while a more limited subset of genes (499) responded to IFN?. Contrary to published reports, administered at non-toxic 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-TNF? antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analysed 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.