Location: Diet, Genomics and Immunology LaboratoryTitle: IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13-dependent Author
Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/20/2012
Publication Date: 2/16/2013
Citation: Yang, Z., Sun, R., Grinchuk, V., Blanco, J.A., Notari, L., Bohl, J.A., Mclean, L.P., Ramalingam, J.R., Wynn, T.A., Urban Jr, J.F., Vogel, S.N., Shea-Donohue, T., Zhao, A. 2013. IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13-dependent. American Journal of Physiology - Gastrointestinal and Liver Physiology. 304(4):G381-389. Interpretive Summary: Products of the immune system can influence non-immune tissues via protein messenger molecules that regulate physiological processes in the intestine. These molecules can be the result of infection and inflammation. The current study showed that a messenger molecule called IL-33, a product of responses to allergic stimuli, can activate intestinal smooth muscle hyper-contractility, increase permeability, and decrease responses to glucose and acetylcholine. It was also able to induce insulin-like growth factor-1 that could increase the amount of intestinal smooth muscle. This work showed how events that activate the immune system such as allergens and parasitic infection can influence intestinal function. The information is important to researchers that study the control of infectious diseases in humans and livestock, and the relationship between parasitic infection, allergic disease, and intestinal responses that affect nutrition and health.
Technical Abstract: IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical “type 2” immune response in the gastrointestinal tract, yet the underlying mechanism(s) remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The current study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88-dependent, but STAT6- and IL-13-independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hyper-contractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on the intestinal epithelial function were STAT6-dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4-, IL-13-, and STAT6-independent. Thus, manipulating IL-33 or related signaling pathways represents a potential therapeutic strategy for treating inflammatory diseases associated with dysregulated intestinal function.