Toll-like receptors 2 and 4 exert opposite effects on the contractile response induced by serotonin in mouse colon: role of serotonin receptors.
What is the central question of this study? The action of Toll-like receptors (TLRs) 2 and 4 on the motor response to serotonin in mouse colon has not previously been reported. What is the main finding and its importance? Toll-like receptors 2 and 4 modulate the serotonin-induced contractile response in mouse colon by modifying the expression of serotonin (5-HT) receptors. Alterations in 5-HT2A and 5-HT2C receptors explain the increase of the response to serotonin in TLR2(-/-) mice. Alterations in 5-HT2C and 5-HT4 receptors explain the suppression of the response to serotonin in TLR4(-/-) mice. The microbiota, through Toll-like receptors (TLRs), may regulate gastrointestinal motility by activating neuroendocrine mechanisms. We evaluated the influence of TLR2 and TLR4 in spontaneous contractions and in the serotonin (5-HT)-induced motor response in mouse colon, and assessed the 5-HT receptors involved. Muscle contractility studies to evaluate the intestinal spontaneous motility and the response to 5-HT were performed in the colon from wild-type (WT), TLR2(-/-) , TLR4(-/-) and TLR2/4 double knockout (DKO) mice. The 5-HT receptor mRNA expression was determined by real-time PCR. The amplitude and frequency of the spontaneous contractions of the colon were smaller in TLR4(-/-) and TLR2/4 DKO mice with respect to WT mice. In WT, TLR2(-/-) and TLR2/4 DKO mice, 100 μm 5-HT evoked a contractile response. The contractile response induced by 5-HT was significantly higher in TLR2(-/-) than in WT mice. In TLR4(-/-) mice, 5-HT did not evoke any contractile response. The mRNA expression of 5-HT2A was increased in TLR2(-/-) and TLR2/4 DKO mice. The 5-HT2C and 5-HT4 mRNA expressions were increased in TLR4(-/-) and TLR2/4 DKO mice. The 5-HT2C mRNA expression was diminished in TLR2(-/-) mice. The 5-HT3 mRNA expression was increased in TLR2(-/-) , TLR4(-/-) and TLR2/4 DKO mice. The 5-HT7 mRNA expression was diminished in TLR2/4 DKO mice. In WT, TLR2(-/-) and TLR2/4 DKO mice, 5-HT2 , 5-HT3 , 5-HT4 and 5-HT7 receptor antagonists reduced or blocked the contractile response evoked by 5-HT. We postulate that TLR2 and TLR4 modulate the serotonin contractile motor response in mouse colon in an opposing manner by modifying the expression of several serotonin receptors.
Departamento de Farmacología y Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet 177, 50013, Zaragoza, Spain.
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Forcén
Departamento de Farmacología y Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet 177, 50013, Zaragoza, Spain.
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Latorre
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009, Zaragoza, Spain.|Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Zaragoza, Spain.
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Pardo
Departamento de Farmacología y Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet 177, 50013, Zaragoza, Spain.|Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Zaragoza, Spain.|Instituto Agroalimentario de Aragón (IA2), Zaragoza, Spain.
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Alcalde
Departamento de Farmacología y Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet 177, 50013, Zaragoza, Spain.|Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Zaragoza, Spain.
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Murillo
Departamento de Farmacología y Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet 177, 50013, Zaragoza, Spain.|Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Zaragoza, Spain.|Instituto Agroalimentario de Aragón (IA2), Zaragoza, Spain.
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0000-0002-5306-9365
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Grasa
D000818:Animals; D003106:Colon / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D012333:RNA, Messenger; D011985:Receptors, Serotonin; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D012701:Serotonin
intestinal motility; microbiota; serotonin