Serotonin activates murine alveolar macrophages through 5-HT2C receptors.
Serotonin (5-HT), known as neuromodulator, regulates immune responses and inflammatory cascades. The expression and function of 5-HT receptors on alveolar macrophages (AM), which are the major fraction of pulmonary immune cells, remain elusive. Therefore, we determined the expression of 5-HT type 2 receptors and investigated the effects evoked by stimulation with 5-HT in AM compared with alveolar epithelial cells (AEC). Quantitative PCR (qPCR) analysis revealed expression of the receptors 5-HT(2A) and 5-HT(2B) in AEC and of 5-HT(2C) in AM. In AM, 5-HT (10(-5) M) induced a rise in intracellular calcium concentration ([Ca(2+)](i)) that was initiated by release of Ca(2+) from intracellular stores and depended on extracellular Ca(2+) in a sustained phase. This 5-HT-induced increase in [Ca(2+)](i) was not observed in AM treated with the 5-HT(2C)-selective inhibitor RS-102221 and in AM derived from 5-HT(2C)-deficient mice. AM stimulated with 5-HT (10(-5) M) showed increased expression of CCL2 (MCP-1) mRNA as assayed by qPCR at 4 h and augmented production of CCL2 protein as determined by dot-blot assay and ELISA at 24 h. Notably, in 5-HT(2C)-deficient AM, CCL2 production was not induced by 5-HT treatment. Moreover, transcriptional responses to 5-HT exposure assayed by microarray experiments were only observed in AM from wild-type animals and not in AM derived from 5-HT(2C)-deficient mice. Taken together, these data demonstrate the presence of functional 5-HT(2C) receptors on AM and suggest a role of 5-HT as novel modulator of AM function. These effects are exclusively driven by the 5-HT(2C) receptor, thereby providing the potential for selective intervention.
Mikulski
Zbigniew
Z
Institute of Anatomy and Cell Biology, Universities of Giessen and Marburg Lung Center, Germany.
Zaslona
Zbigniew
Z
Cakarova
Lidija
L
Hartmann
Petra
P
Wilhelm
Jochen
J
Tecott
Laurence H
LH
Lohmeyer
Juergen
J
Kummer
Wolfgang
W
D000818:Animals; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000378:metabolism*; D051379:Mice; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
C107821:8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D013141:Spiro Compounds; D013449:Sulfonamides; D012701:Serotonin; D002118:Calcium