Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function

Madden, Kathleen B.; Whitman, Lucia; Sullivan, Connor; Gause, William C.; Urban, Joseph F.; Katona, Ildy M.; Finkelman, Fred D.; Shea‐Donohue, Terez

doi:10.4049/jimmunol.169.8.4417

Cited by 154 publications

(178 citation statements)

References 36 publications

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“…IL-25 is a potent inductor for the production of IL-4, IL-5, and IL-13 (8). These Th2 cytokines, particularly IL-4 and IL-13, previously have been reported to cause a number of changes in intestinal epithelial functions, such as balance of ion, mucosal fluids absorption (15), and increase in intestinal smooth muscle contraction (16). IL-13 was found primarily to mediate massive histological changes in the gastrointestinal mucosa of mice treated with rIL-25 (8).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Recombinant IL-25 on the Development of Dextran Sulfate Sodium-Induced Experimental Colitis in Mice

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Recombinant IL-25 on the Development of Dextran Sulfate Sodium-Induced Experimental Colitis in Mice

et al. 2008

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“…Their further work (37) revealed an increase in chloride ion secretion by infected tissue in response to externally applied histamine, serotonin, and prostaglandin E2, three factors produced by mast cells. Equally, Madden et al (38) showed that WT mice but not mast cell-deficient mice respond to IL-4 by increasing chloride secretion after either histamine or prostaglandin E2 stimulation in vitro. Their data support our demonstration that mast cells are crucial for increased mucosal permeability during T. spiralis infection.…”

Section: Discussionmentioning

confidence: 99%

Mast cells disrupt epithelial barrier function during enteric nematode infection

McDermott

Bartram²,

Knight³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

299

245

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We have investigated the influence of mast cells on the barrier function of intestinal epithelium during nematode infection. Trichinella spiralis infection induces a strong type 2 cytokinemediated inflammation, resulting in a critical mucosal mastocytosis that is known to mediate expulsion of the parasites from the intestine. The host response to infection is also characterized by an increase in mucosal leakiness. We show here that intestinal epithelial permeability is markedly elevated during infection, with kinetics that mirror the adaptive immune response to primary and secondary infection. Furthermore, we have identified degradation of the tight junction protein, occludin, thereby providing a mechanism for increased paracellular permeability during helminth infection. We further demonstrate by using anti-c-kit antibody and IL-9 transgenic mice that mast cells are directly responsible for increasing epithelial paracellular permeability and that mice deficient in a mast cell-specific protease fail to increase intestinal permeability and fail to expel their parasite burden. These results provide the mechanism whereby mucosal mast cells mediate parasite expulsion from the intestine.T he adult stage of the nematode Trichinella spiralis resides within enterocytes of the jejunum. During parasite infection characteristic changes occur in the small intestine (1). It has long been known that the gut becomes edematous and inflamed, with these responses peaking at the time of parasite expulsion from the host, but the precise mechanisms involved have remained obscure. Infection induces leakiness in the intestinal epithelium that is considered to be a host defense mechanism against the parasite (the leak-lesion hypothesis) (2).We hypothesize that an increase in epithelial paracellular permeability resulting in the loss of parasites is a direct consequence of adaptive immunity. T. spiralis elicits a strong T helper 2 response resulting in intestinal goblet cell hyperplasia, eosinophilia, and a profound mucosal mastocytosis (3-5). Efficient parasite expulsion depends on CD4 ϩ T cells through control of the critical mast cell response (6). In the absence of intestinal mast cells the loss of parasites is markedly delayed (7). The mechanism by which mast cells induce parasite expulsion is unknown and is the focus of this study.Changes in epithelial paracellular permeability during the course of T. spiralis infection in mice and the role that the mast cell may play in inducing these changes were investigated. By depleting mast cells with anti-c-kit antibodies or by using IL-9 transgenic mice that overexpress mast cells (8), we present compelling evidence that mast cells are the key mediators of increased mucosal permeability. To understand further the action of mast cells on intestinal epithelium, we have infected mice deficient in mouse mast cell protease-1 (mMCP-1) that had been shown previously to delay parasite expulsion (9) and investigated whether this mast cell-specific proteinase is involved in increased epithelial perm...

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“…Ϫ Secretion-IL-13 is a key Th2 cytokine that has been implicated in aspects of intestinal function (7,27). To delineate the effect of increased intestinal IL-13 on small intestinal barrier function, we examined the resistance across the mucosa (resistance) and ion conductance through ex vivo measurements of I sc across the jejunum of iIL-13Tg and littermate WT mice.…”

Section: Overexpression Of Il-13 In the Small Intestine Up-regulates CLmentioning

confidence: 99%

Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

Wu¹,

Ahrens²,

Osterfeld³

et al. 2011

Journal of Biological Chemistry

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Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral 3 apical Cl ؊ ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl

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Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function

Cited by 154 publications

References 36 publications

Inhibitory Effect of Recombinant IL-25 on the Development of Dextran Sulfate Sodium-Induced Experimental Colitis in Mice

Inhibitory Effect of Recombinant IL-25 on the Development of Dextran Sulfate Sodium-Induced Experimental Colitis in Mice

Mast cells disrupt epithelial barrier function during enteric nematode infection

Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

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