Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility.
Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility.
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DOI：
10.1053/j.gastro.2006.05.013
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发表时间：
2006-08
期刊：
影响因子：
29.4
通讯作者：
Aiping Zhao;J. Urban;M. Morimoto;Justin E. Elfrey;K. Madden;F. Finkelman;T. Shea-Donohue
中科院分区：
文献类型：
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作者：
Aiping Zhao;J. Urban;M. Morimoto;Justin E. Elfrey;K. Madden;F. Finkelman;T. Shea-Donohue
背景与目的肠线虫感染诱导平滑肌过度收缩，这依赖于白细胞介素(IL)-4和IL-13激活信号换能器和转录激活因子（STAT） 6。5-羟色胺（5-HT）参与肠道功能的生理调节。本研究探讨了5-羟色胺及其受体在线虫诱导的肠平滑肌过度收缩中的作用。方法小鼠感染巴西尼波圆线虫（N brasiliensis）或多回Heligmosomoides polygyrus （H polygyrus）或静脉注射IL-13。空肠部分悬浮在器官浴中，在特定5-HT拮抗剂存在或不存在的情况下，测定平滑肌对5-HT的反应。实时定量聚合酶链反应检测IL-4、IL-13和5-HT受体信使RNA的表达。结果5-羟色胺诱导野生型（WT）小鼠平滑肌适度收缩，而5-羟色胺拮抗剂酮色胺未改变。巴西芽胞杆菌感染引起平滑肌对5-HT的过度收缩，这种收缩被5-HT（2A）拮抗剂所消除，而其他5-HT拮抗剂则不能消除。感染诱导的5-HT2A表达上调与平滑肌对5-HT的过度收缩有关。在IL-4（-/-）小鼠中也观察到感染诱导的WT小鼠5-HT2A的上调，但在IL-13（-/-）或STAT6（-/-）小鼠中未见。此外，IL-13或多回H感染也增强了WT小鼠平滑肌对5-HT和5-HT2A表达的反应。这些数据表明，5-HT2A是STAT6激活下游介导平滑肌功能变化的分子之一。5-HT2A是调节免疫介导的肠蠕动作用的一种新的治疗靶点。
BACKGROUND & AIMS Enteric nematode infection induces a smooth muscle hypercontractility that depends on interleukin (IL)-4 and IL-13 activation of the signal transducer and activator of transcription (STAT) 6. Serotonin (5-HT) is involved in the physiologic regulation of gut function. The present study investigated the contribution of 5-HT and its receptors in nematode-induced intestinal smooth muscle hypercontractility. METHODS Mice were infected with Nippostrongylus brasiliensis (N brasiliensis) or Heligmosomoides polygyrus (H polygyrus) or injected intravenously with IL-13. Segments of jejunum were suspended in organ baths, and smooth muscle responses to 5-HT were determined in the presence or absence of specific 5-HT antagonists. IL-4, IL-13, and 5-HT receptor messenger RNA expressions were determined by real-time quantitative polymerase chain reaction. RESULTS 5-HT evoked a modest contraction of smooth muscle in wild-type (WT) mice that was unaltered by the 5-HT2A antagonist ketanserin. N brasiliensis infection induced a smooth muscle hypercontractility to 5-HT that was abolished by 5-HT(2A) antagonists but not by other 5-HT antagonists. Infection-induced up-regulation of 5-HT2A expression was correlated with the smooth muscle hypercontractility to 5-HT. The infection-induced up-regulation of 5-HT2A in WT mice was observed also in IL-4(-/-) mice but was not seen in IL-13(-/-) or STAT6(-/-) mice. In addition, smooth muscle responses to 5-HT and 5-HT2A expression in WT mice were also enhanced by IL-13 or H polygyrus infection. CONCLUSIONS These data show that 5-HT2A is one of the molecules downstream from STAT6 activation that mediates changes in smooth muscle function. 5-HT2A represents a novel therapeutic target for modulating immune-mediated effects on intestinal motility.