The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release.
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-HTR(3), 5-HTR(4), and 5-HTR(7) 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-HTR(4) and 5-HTR(7). The mRNA expression level of the ligand-gated cation channel 5-HTR(3) 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-HTR(3)-dependent Ca(2+) influx in immature and mature DC. Moreover, we revealed that 5-HTR(1) and 5-HTR(2) receptor stimulation induced intracellular Ca(2+) mobilization via G(i/o) proteins in immature, but not mature, DC. Activation of 5-HTR(4) and 5-HTR(7) induced cAMP elevation in mature DC. Functional studies indicated that activation of 5-HTR(4) and 5-HTR(7) enhanced the release of the cytokines IL-1beta and IL-8, while reducing the secretion of IL-12 and TNF-alpha 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.
Idzko
Marco
M
Department of Pneumology, University of Freiburg, Freiburg, Germany.
Panther
Elisabeth
E
Stratz
Christian
C
Müller
Tobias
T
Bayer
Hannes
H
Zissel
Gernot
G
Dürk
Thorsten
T
Sorichter
Stephan
S
Di Virgilio
Francesco
F
Geissler
Michael
M
Fiebich
Bernd
B
Herouy
Yared
Y
Elsner
Peter
P
Norgauer
Johannes
J
Ferrari
Davide
D
D001693:Biological Transport, Active / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D020033:Protein Isoforms; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D012701:Serotonin; D000242:Cyclic AMP; D002118:Calcium