|Shea donohue, P|
Submitted to: Journal of Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 9/1/2002
Publication Date: 10/15/2002
Citation: Madden, K., Whitman, L., Sullivan, C., Gause, W., Donaldson, D., Urban Jr, J.F., Katona, I., Finkelman, F., Shea Donohue, P.T. 2002. Role of stat6 and mast cells in il4-and il-13-induced alterations in murine intestinal epithelial cell function. Journal of Immunology. 169:4417-4432 (2002) Interpretive Summary: Intestinal worm parasites infect over one billion people worldwide and cause significant economic losses in livestock. They can interfere with intestinal function by changing nutrient metabolism and require activation of the immune system to eliminate the infection. A detailed examination of the mechanism of intestinal secretion and absorption during infection with worms can provide information on vaccines to control infection and agents that restore normal digestion in the gut. Two particular agents that have similar function on intestinal cells were examined in detail. These included interleukin-4 (IL-4) and IL-13. These molecules were shown to affect intestinal cell resistance (a measure of cell permeability), secretion and absorption of simple sugars. Both agents decreased resistance, sugar absorption, and secretion of small molecules into the gut. However, responses to certain natural intestinal agents that regulate the level of intestinal secretion were directly affected by IL-13 but indirectly by IL-4. These results suggest that the interaction of these two agents are complex and often require other cells and stimulants to effectively regulate intestinal metabolism and the elimination of worm infection. Because these agents are also a normal feature of allergy, the information on their function in the intestine could provide ways of controlling food allergies that often complicate the eating habits of millions of people worldwide.
Technical Abstract: Gastrointestinal nematode infections generally invoke a type 2 cytokine response, characterized by the production of IL-4, IL-5, IL-9, and IL-13. Among these cytokines, IL-4 and IL-13 exhibit a functional overlap that can be explained by sharing of a common receptor or receptor component (IL-4Ra. Binding of IL-4 by either the type 1 or type 2 IL-4R, or of IL-13 by the type 2 IL-4R, initiates Jak-dependent tyrosine phosphorylation of the IL-4Ra chain and the transcription factor, Stat6. In the present study we investigated (1) whether IL-13 has effects on intestinal epithelial cells similar to those observed with IL-4, and (2) whether the effects of IL-4 and IL-13 depend on Stat6 signaling and/or mast cells. BALB/c,Stat6-/-, and mast cell-deficient W/Wv mice or their +/+ littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or with IL-13 for seven days. Segments of jejunum were mounted in Ussing chambers to measure mucosal permeability, chloride secretion in response to PGE2, histamine, 5-hydroxytryptamine (5-HT), or acetylcholine, and Na+-linked glucose absorption. IL-4C and IL-13 increased mucosal permeability, decreased glucose absorption, and decreased chloride secretion in response to 5-HT. These effects were dependent on Stat6 signaling. Responses to PGE2 and histamine, which were dependent on mast cells and Stat6, were enhanced by IL-4C, but not by IL-13. The effects of IL-4 and IL-13 on intestinal epithelial cell function may play a critical role in host protection.