|Zhao, Aiping -|
|Sun, Rex -|
|Stiltz, Jennifer -|
|Morimoto, Motoko -|
|Notari, Luigi -|
|Madden, Kathleen -|
|Ramalingam, Thiru -|
|Wynn, Thomas -|
|Shea-Donohue, Terez -|
Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 25, 2010
Publication Date: December 1, 2010
Citation: Zhao, A., Urban Jr, J.F., Sun, R., Stiltz, J., Morimoto, M., Notari, L., Madden, K., Ramalingam, T., Wynn, T., Shea-Donohue, T. 2010. Critical role of intestinal epithelial cell-derived IL-25 in enteric nematode infection-induced changes in intestinal function. Journal of Immunology. 185:6921-6929. Interpretive Summary: Parasitic worm infections are convenient models to examine allergic responses in the intestine and lung that represent responses to food and aerosol allergens because of the similar nature of the immune response that is induced. A key question is how the worm, or allergen, initiates changes at the surface of the tissue to activate immune function and physiological modification. The current study describes a new regulatory molecule called IL-25 that is produced by epithelial cells that line these tissues and, in turn, activates other regulatory molecules like IL-13 that further enhance the response to cause changes in smooth muscle and epithelial cell secretion. This work will be of interest to nutritionists who study food allergy, clinicians that evaluate intestinal function, and scientists interested in the regulation of harmful side effects of parasitic infection and allergic disease on host immunity and nutrient absorption.
Technical Abstract: The current study investigated the mechanism of immune regulation of IL-25 and the contribution of IL-25 to nematode infection-induced alterations in intestinal smooth muscle and epithelial cell function. Mice were infected with an enteric nematode or injected with IL-25 or IL-13. In vitro smooth muscle contractility was performed to assess muscle responses to acetylcholine, serotonin, and electrical field stimulation, as well as spontaneous contractions. Mucosal function was determined by challenging the muscle-free mucosa mounted in Ussing chambers for epithelial secretion, or in micro-snap well for trans-epithelial resistance. Gene expression of major cytokines were determined via real-time PCR or viewed by immune fluorescent staining. Epithelial cells, but not immune cells, constitute the major source of IL-25 in the small intestine constitutively and during nematode infection. Infection-induced up-regulation of IL-25 expression depended upon IL-13 activation of Stat6. IL-25 deficiency in mice caused an impaired Th2 immunity against N. brasiliensis infection, associated with an abolished intestinal smooth muscle hyper-contractility and reduced mucosal functional response, whereas exogenous IL-25 induced characteristic changes in intestinal function similar to that induced by nematode infection. Exogenous IL-25 was unable to restore the impaired host immunity against N. brasiliensis infection in IL-13-/- mice. Thus, epithelial-derived IL-25 plays a critical role in nematode infection-induced changes in intestinal function and IL-13 is the major Th2 cytokine responsible for IL-25-mediated changes in gut function.