|Shea Donohue, P|
Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/15/2004
Publication Date: 5/1/2004
Citation: Madden, K., Auyeung, K., Zhao, A., Gause, W., Finkelman, F., Katona, I., Urban Jr, J.F., Shea Donohue, P.T. 2004. Enteric nematodes induce stereotypic stat6-dependent alterations in intestinal epithelial cell function. Journal of Immunology. 172:5616-5621 (2004) Interpretive Summary: The host response to food allergens is similar to that against gastrointestinal nematode or worm parasites. In fact, the basis of allergic disease may be that allergens have substituted for worm products that are the driving force in the evolutionary development of the immune system to control worm infection. Developed countries with Westernized diets have an epidemic of allergy to food and environmental proteins, while worm infections have largely been eliminated as a health concern. In order to understand how diet may affect the development and expression of allergic responses at mucosal surface, we have developed experimental systems to measure changes in immunological and physiological responses to different intestinal worm infections. The results show that worms with very different life cycles and developmental stages in the host induce similar changes in secretions and smooth muscle contractility that are linked to specific immune molecules. This response has been coined the 'weep and sweep' response because it is characterized as a flushing of worms from the intestine. The response is comparable to that observed during an allergic response to food allergens and identifies mechanisms that can be targeted to reduce the intensity or minimize the reactivity of responses to food allergens. Attempts will be made to develop dietary strategies that are useful in the management of localized allergic response in the intestine. This work is of interest to other scientists that study basic mechanisms of allergy and responses to infectious agents that invade the intestine, and will impact the development of targets for control of these responses in livestock and man.
Technical Abstract: Infection with gastrointestinal (GI) nematodes exerts profound effects on both the immune and physiological responses of the host. We have shown previously that a secondary infection of BALB/c mice with the GI nematode Hp increases mucosal permeability while decreasing sodium-linked glucose absorption, and that these effects are mediated by IL-4. More recently, we have demonstrated that the T helper 2 (Th2) cytokines, IL-4 and IL-13, induce similar changes in intestinal epithelial cell permeability, absorption, and secretion, and that these alterations are STAT6-dependent. In the current study, we investigated whether these perturbations of intestinal epithelial cell function were (i) limited to infection with Hp; (ii) dependent upon STAT6; and (iii) attributed to direct effects on the epithelial cells themselves, or regulated indirectly through effects on enteric nerves. Our results demonstrate that infection of BALB/c mice with three different GI nematodes (Hp, Nb, and Tsp) alters intestinal epithelial function, by decreasing resistance, glucose absorption, and secretory responses to 5-HT and acetylcholine, two critical mediators in the sub mucosal reflex pathway. These modified responses are dependent on STAT6, and are the result of both direct effects and indirect effects mediated through enteric nerves.