Immunomodulatory effects mediated by serotonin

Abstract

Serotonin (5-HT) induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a) membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b) downstream signaling transduction proteins; and (c) enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases.

Figure 1

Metabolic pathways associated with 5-HT. The metabolic pathways branching from the catabolism of tryptophan are shown. Green and brown branches show kynurenine pathways from tryptophan. The dark blue branch displays the 5-HT generation pathway while the red branch displays the melatonin generation pathway (solid line) and the melatonin catabolism pathway (dashed lines). The 5-HT catabolism pathways are depicted in blue, purple, and cyan dotted lines. The most relevant compounds are circled with dotted lines and underlined compounds have no demonstrated effects. An additional catabolic pathway marked in pink from 5-hydroxy-L-tryptophan generates 5-hydroxy-kynurenine and 5-hidroxy-kynurenamine family compounds (paths C05648 and C05647), which have no demonstrated biological effects. The compounds in these pathways are denoted by their “Kyoto Encyclopedia of Genes and Genomes” (KEGG) code (http://www.genome.jp/kegg/). Enzymes with their classification codes (EC, http://www.chem.qmul.ac.uk/iubmb/enzyme/) and UNIPROT gene names are shown in squares. The shading arrows show the most studied pathways.