5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes.
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-HTR(1E)), 5-HTR(2A), 5-HTR(3), 5-HTR(4) and 5-HTR(7) could be revealed. Functional studies showed that 5-HT modulates the release of IL-1beta, IL-6, IL-8/CXCL8, IL-12p40 and tumor necrosis factor-alpha (TNF-alpha), while it has no effect on the production of IL-18 and IFN-gamma 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-1beta and TNF-alpha. Pharmacological studies with isotype-selective receptor agonists allowed us to show that 5-HTR(3) subtype up-regulates the LPS-induced production of IL-1beta, IL-6 and IL-8/CXCL8, while it was not involved in TNF-alpha and IL-12p40 secretion. Furthermore, activation of the G(s)-coupled 5-HTR(4) and 5-HTR(7) subtypes increased intracellular cyclic AMP (cAMP) and secretion of IL-1beta, IL-6, IL-12p40 and IL-8/CXCL8, while, on the contrary, it inhibited LPS-induced TNF-alpha release. Interestingly, 5-HTR(1) and 5-HTR(2) 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-HTR(3), 5-HTR(4) and 5-HTR(7) subtypes.
Dürk
Thorsten
T
Department of Pneumology, University Medical Clinic, University of Freiburg, Germany.
Panther
Elisabeth
E
Müller
Tobias
T
Sorichter
Stephan
S
Ferrari
Davide
D
Pizzirani
Cinzia
C
Di Virgilio
Francesco
F
Myrtek
Daniel
D
Norgauer
Johannes
J
Idzko
Marco
M
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010078:Oxazines / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D011985:Receptors, Serotonin / Q000145:classification / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018925:Chemokines; D016207:Cytokines; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D010078:Oxazines; D010636:Phenols; D010880:Piperidines; C475107:RS 39604; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin; D012313:RNA; C070671:azasetron; D011407:Propane