5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes

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Abstract
The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is released at peripheral sites from activated enterochromaffin cells, mast cells and platelets. In this study we analyzed the biological activity and intracellular signaling of 5-HT in human monocytes. By reverse transcription (RT) and PCR, messenger RNA (mRNA) expression of 5-HT receptor 1E (5-HTR1E), 5-HTR2A, 5-HTR3, 5-HTR4 and 5-HTR7 could be revealed. Functional studies showed that 5-HT modulates the release of IL-1β, IL-6, IL-8/CXCL8, IL-12p40 and tumor necrosis factor-α (TNF-α), while it has no effect on the production of IL-18 and IFN-γ in LPS-stimulated human blood monocytes. Moreover, RT and PCR revealed that 5-HT modulated mRNA levels of IL-6 and IL-8/CXCL8, but did not influence mRNA levels of IL-1β and TNF-α. Pharmacological studies with isotype-selective receptor agonists allowed us to show that 5-HTR3 subtype up-regulates the LPS-induced production of IL-1β, IL-6 and IL-8/CXCL8, while it was not involved in TNF-α and IL-12p40 secretion. Furthermore, activation of the Gs-coupled 5-HTR4 and 5-HTR7 subtypes increased intracellular cyclic AMP (cAMP) and secretion of IL-1β, IL-6, IL-12p40 and IL-8/CXCL8, while, on the contrary, it inhibited LPS-induced TNF-α release. Interestingly, 5-HTR1 and 5-HTR2 agonists did not modulate the LPS-induced cytokine production in human monocytes. Our results point to a new role for 5-HT in inflammation by modulating cytokine production in monocytes via activation of 5-HTR3, 5-HTR4 and 5-HTR7 subtypes.