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

• Published in: International immunology 2005-05, Vol.17 (5), p.599-606
• Main Authors: Dürk, Thorsten, Panther, Elisabeth, Müller, Tobias, Sorichter, Stephan, Ferrari, Davide, Pizzirani, Cinzia, Di Virgilio, Francesco, Myrtek, Daniel, Norgauer, Johannes, Idzko, Marco
• Format: Article
• Language: English
• Subjects: 2-MHT 2-methoxytryptamine; 2Me5-HT N-methyl-5-hydroxytryptamine; 5-HT 5-hydroxytryptamine; 8-HDPAT 8-hydroxy-DPAT-hydrobromide; AP 3-(4-Allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; BRL 54443 3-(1-methyl-piperidin-4-yl)-1H-indol-5-ol maleate salt; cAMP cyclic AMP; Cells, Cultured; Chemokines - biosynthesis; CT cycle threshold; Cytokines - biosynthesis; DOI R-(−)-DOI-hydrochloride; Free Radical Scavengers - pharmacology; Humans; IL-1β; IL-6; IL-8/CXCL8; Lipopolysaccharides - pharmacology; MDL 12330A cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en- 2-amine; monocytes; Monocytes - drug effects; Monocytes - immunology; mRNA messenger RNA; Oxazines - pharmacology; Phenols - pharmacology; Piperidines - pharmacology; Propane - analogs & derivatives; Propane - pharmacology; Receptors, Serotonin - classification; Receptors, Serotonin - metabolism; RNA - metabolism; RS 39604 RS 39604 hydrochloride; RT reverse transcription; SB 269970 SB 269970 hydrochloride; serotonin; Serotonin - pharmacology; Serotonin Antagonists - pharmacology; Sulfonamides - pharmacology; TNF-α tumor necrosis factor-α; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Y-25130 Y-25130 hydrochloride
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxh242

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.