Submitted to: Gastroenterology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/1/2005
Publication Date: 8/1/2006
Citation: Zhao, A., Urban, Jr, J.F., Morimoto, M., Elfrey, J., Madden, K., Finkelman, F., Shea-Donohue, T. 2006. Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hyper contractility. Gastroenterology. 131(2):568-578 Interpretive Summary: Serotonin (5-HT) is an important chemical transmitter in both the central and peripheral nerve system and impacts a number of functions including appetite, mood, and perception. The gut is the largest source of 5-HT and contains at least 15 receptor subtypes located on neurons, smooth muscle and epithelial cells that are involved in gut mucosa and smooth muscle function. Parasitic worm infection in the intestine act like food allergens because of the nature of the immune response that is induced including the release of the immune mediators IL-4 and IL-13. These mediators are also induced during allergic disease and regulate a number of immune and non-immune functions. Food particles, and worms, activate the release of 5-HT in the intestine due contact with enterochromaffin cells in the gut. One unanswered question was the relationship between IL-4 and IL-13 and the expression of receptors for 5-HT. We observed that worm infection primarily induced 5-HT receptor 2A through an IL-13 but not IL-4 activated mechanism. This is of interest because recent studies have show a marked increase in 5-HT in a subset of patients with Irritable Bowel Syndrome (IBS). The regulation of 5-HT receptors by worm infection can provide important information on the role of the 5-HT and specific receptor interactions that lead to disease in the intestine. This work will be of interest to nutritionists who study food allergy, clinicians that evaluate IBD, and scientists interested in the role of parasitic infection in host immunity and nutrient absorption.
Technical Abstract: Enteric nematode infection induces smooth muscle hyper contractility that depends on interleukin (IL)-4 and IL-13 activating the signal transducer and activator of transcription (STAT) 6. Serotonin (5-HT) is involved in the physiological regulation of gut function. We investigated the contribution of 5-HT and its receptors in nematode induced intestinal smooth muscle hyper contractility. Mice were infected with Nippostrongylus brasiliensis; Heligmosomoides polygyrus; or injected i.v. with IL-13 for seven days. 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 mRNA expression was determined by real-time quantitative PCR. 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, however, induced a smooth muscle hyper contractility to 5-HT that was abolished by ketanserin, but not by other 5-HT antagonists. Infection-induced up-regulation of 5-HT2A expression was correlated temporally with the smooth muscle hyper contractility to 5-HT. The infection-induced up regulation of 5-HT2A in WT mice was also observed 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 target for modulating immune-mediated effects on intestinal motility.