Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2005
Publication Date: 8/15/2005
Citation: Zao, A., Morimoto, M., Dawson, H., Elfrey, J.E., Madden, K.B., Gause, W.C., Min, B., Finkelman, F.D., Urban, J.F. Jr., Shea-Donohue, T. 2005. Immune regulation of protease-activated receptor-1 expression in murine small intestine during nippostrongylus brasiliensis infection. Journal of Immunology. 175(4):2563-2569. Interpretive Summary: Intestinal worm parasites infect >billion people worldwide, including several million in the U.S., and cause significant economic loss in livestock. The parasites interfere with nutrient utilization and activate the host immune system. Examination of how smooth muscle lining the intestine contracts during worm infection can provide information on how to control infection and restore normal digestive function. Two agents that have similar activity on smooth muscle cells are interleukin-4 (IL-4) and IL-13. These molecules increase smooth muscle contractility to nerve stimulation with IL-13 having a relatively greater effect that was dependent on Stat6; a molecule needed in intra cellular regulatory pathways. Protease-activated receptors (PAR) are activated by enzymes released during the process of tissue repair and have been shown to be expressed during allergic disease. The disease process associated with allergy and immunity to worm infection is comparable. We, therefore, were interested in the expression of PAR during worm infection and hypothesized that PAR would play a role in resistance to infection. The studies showed that PAR-1 expression was increased during infection and contributed to smooth muscle contraction during expulsion of the worm. The mechanism was linked to IL-13 and Stat6; supporting the common pathway induced by allergy and worms. These results suggest that PAR could be a target of dietary interventions. This work will primarily benefit scientists in their effort to control worm infection without affecting metabolism and growth.
Technical Abstract: Infection with gastrointestinal nematodes exerts profound effects on both immune and physiological responses of the host. Helminth infection induces a hyper-contractility of intestinal smooth muscle that contributes to worm expulsion that is dependent on the Th2 cytokines, IL-4 and IL-13. Protease-activated receptors are expressed throughout the gut and activation of PAR-1 was observed in asthma, a Th2 driven pathology. In the current study we investigated the physiologic and immunologic regulation of PAR-1 in the small intestine specifically (i) the effect of PAR-1 agonists on small intestinal smooth muscle contractility; (ii) the effects of helminth infection on PAR-1 responses; (iii) the role of IL-13 and IL-4 in Nippostrongylus brasiliensis infection-induced alterations in PAR-1 responses; and (iv) the STAT6-dependence of these responses. We demonstrate that PAR-1 activation induces contraction of murine intestinal smooth muscle that is enhanced during helminth infection. This hyper-contractility is associated with an elevated expression of PAR-1 mRNA and protein. Nippostrongylus brasiliensis-induced changes in PAR-1 function and expression were seen in IL-4-deficient mice, but not in IL-13- or STAT6-deficient mice, indicating the dependence of IL-13 on STAT6 signaling.