Contribution of 5-HT 2A Receptor in Nematode Infection-Induced Murine Intestinal Smooth Muscle Hypercontractility

Abstract

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. 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. 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. 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.