title: Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation.
abstract: TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.
authors.affiliation: Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza. Spain.|RNA-Mediated Mechanisms of Disease, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School. Exeter. United Kingdom.
authors.forename: Eva
authors.identifier: http://orcid.org/0000-0002-5797-3909
authors.initials: E
authors.lastname: Latorre
authors.affiliation: Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza. Spain.|Instituto Agroalimentario de Aragón-IA2- (Universidad de Zaragoza-CITA), Zaragoza, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Layunta
authors.affiliation: Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza. Spain.|Instituto Agroalimentario de Aragón-IA2- (Universidad de Zaragoza-CITA), Zaragoza, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Grasa
authors.affiliation: Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza. Spain.|Instituto Agroalimentario de Aragón-IA2- (Universidad de Zaragoza-CITA), Zaragoza, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Castro
authors.affiliation: Departamento Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Pardo
authors.affiliation: Servicio de Sistema Digestivo. Hospital Clínico Universitario "Lozano Blesa", Instituto de Investigación Sanitaria de Aragón (IIS); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Zaragoza, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gomollón
authors.affiliation: Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza. Spain.|Instituto Agroalimentario de Aragón-IA2- (Universidad de Zaragoza-CITA), Zaragoza, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Alcalde
authors.affiliation: Departamento Farmacología y Fisiología, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Zaragoza. Spain.|Instituto Agroalimentario de Aragón-IA2- (Universidad de Zaragoza-CITA), Zaragoza, Spain.
authors.forename: José E
authors.initials: JE
authors.lastname: Mesonero
mesh_terms: D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D012701:Serotonin