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The Serotoninergic Receptors of Human Dendritic Cells: Identification and Coupling to Cytokine Release ¹

Marco Idzko^2,*, Elisabeth Panther^2,, Christian Stratz^*, Tobias Müller^*, Hannes Bayer^*, Gernot Zissel^*, Thorsten Dürk^¶, Stephan Sorichter^*, Francesco Di Virgilio^||, Michael Geissler, Bernd Fiebich, Yared Herouy, Peter Elsner^¶, Johannes Norgauer^¶ and Davide Ferrari^3,||

Departments of ^* Pneumology, Gastroenterology, Psychiatry, Dermatology, University of Freiburg, Freiburg, Germany; ^¶ Department of Dermatology, University of Jena, Jena, Germany; and ^|| Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy

The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is stored at peripheral sites in mast cells and released from this peripheral source upon IgE cross-linking. In this study, we investigated the expression of serotoninergic receptors (5-HTR), the signaling pathway, and biological activity of 5-HT on human dendritic cells (DC), showing that immature and mature DC expressed mRNA for different serotoninergic receptors. Thereby, the mRNA of 5-HTR_1B, 5-HTR_1E, 5-HTR_2A, 5-HTR_2B, one splicing variant of the 5-HTR₃, 5-HTR₄, and 5-HTR₇ receptors were detected. Immature DC preferentially expressed mRNA for the heptahelical 5-HTR_1B, 5-HTR_1E, and 5-HTR_2B receptors, while mature DC mostly expressed 5-HTR₄ and 5-HTR₇. The mRNA expression level of the ligand-gated cation channel 5-HTR₃ and the heptahelical 5-HTR_2A did not significantly change during maturation. Isotype-selective receptor agonists allowed us to show that 5-HT stimulated 5-HTR₃-dependent Ca²⁺ influx in immature and mature DC. Moreover, we revealed that 5-HTR₁ and 5-HTR₂ receptor stimulation induced intracellular Ca²⁺ mobilization via G_i/o proteins in immature, but not mature, DC. Activation of 5-HTR₄ and 5-HTR₇ induced cAMP elevation in mature DC. Functional studies indicated that activation of 5-HTR₄ and 5-HTR₇ enhanced the release of the cytokines IL-1 and IL-8, while reducing the secretion of IL-12 and TNF- in mature DC. In summary, our study shows that 5-HT stimulated, in a maturation-dependent manner, different signaling pathways in DC. These data point to a role for 5-HT in regulating the immune response at peripheral sites.

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