Cutting Edge: IL-4 Receptor Expression by Non-Bone Marrow-Derived Cells Is Required to Expel Gastrointestinal Nematode Parasites

Urban, Joseph F.; Noben-Trauth, Nancy; Schopf, Lisa; Madden, Kathleen B.; Finkelman, Fred D.

doi:10.4049/jimmunol.167.11.6078

Cited by 90 publications

(92 citation statements)

References 23 publications

(19 reference statements)

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“…They also showed that IL-4-deficient mice failed to expel if treated with sIL-13R␣2, thus indicating that both IL-13 and IL-4 are important in resistance to this nematode. Interestingly, IL-4R␣ expression by nonhemopoietic cells is enough to expel N. brasiliensis from the intestine, whereas expulsion of T. spiralis requires receptor expression by both bone marrow-and nonbone marrow-derived cells (19). This indicates that IL-13 and/or IL-4 can directly stimulate intestinal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, distinctive changes in villus and crypt architecture occur that may also be an attempt by the host to drive out the parasite by diminishing the area available for habitation (18). T cells are required for worm expulsion from the gut, but this is not IL-4 dependent, because mice genetically deficient for IL-4 can expel normally (19). However, expulsion is inhibited in mice deficient in the IL-4/IL-13 signaling molecules IL-4R␣ or STAT6, suggesting a role for IL-13 (19,20).…”

mentioning

confidence: 99%

“…T cells are required for worm expulsion from the gut, but this is not IL-4 dependent, because mice genetically deficient for IL-4 can expel normally (19). However, expulsion is inhibited in mice deficient in the IL-4/IL-13 signaling molecules IL-4R␣ or STAT6, suggesting a role for IL-13 (19,20). IL-13 is certainly critical for expulsion of another gastrointestinal nematode, Nippostrongylus brasiliensis, which inhabits the lumen of the small intestine (21), and resolution of Trichuris muris infection of the large bowel is also dependent on IL-13 via the production of TNF-␣ (22).…”

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confidence: 99%

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Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

McDermott

Humphreys

Forman

et al. 2005

The Journal of Immunology

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IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays a major role in the control of gut nematode infection and associated immunopathology. The current paradigm is that these effects are due to T cell-derived IL-13. We show in this study that an innate source of IL-13, the intraepithelial NK cell, is responsible for the disruption of intestinal tissue architecture and induction of goblet cell hyperplasia that characterizes infection with the intestinal helminth Trichinella spiralis. IL-13 or IL-4Rα (but not IL-4) null mice failed to induce intestinal pathology. Unexpectedly, SCID and athymic mice developed the same pathology found in immunocompetent mice following infection. Moreover, immunodeficient mice expressed IL-13 in the intestine, and abnormal mucosal pathology was reduced by in vivo administration of a soluble IL-13 antagonist. IL-13 expression was induced in non-T intraepithelial CD3− NK cells. Epithelial cells expressed the IL-13 signaling receptor, IL-13Rα1, and after infection, IL-4Rα. Furthermore, the soluble IL-13 decoy receptor IL-13Rα2, which regulates IL-13 responses, was also induced upon infection. These data provide the first evidence that intestinal tissue restructuring during helminth infection is an innate event dependent on IL-13 production by NK cells resident in the epithelium of the intestine.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

McDermott

Humphreys

Forman

et al. 2005

The Journal of Immunology

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“…It remains to be determined whether STAT6 signaling is required to induce mast cells to release specific mediators that promote increased responsiveness to PGE 2 and histamine, or whether there is a separate, STAT6-dependent effect of IL-4 on intestinal epithelial cells that acts with a STAT6-independent mast cell effect to increase intestinal epithelial responsiveness. In support of the latter possibility, IL-4 has been shown to act through a STAT6-dependent mechanism to: 1) increase responsiveness to platelet-activating factor, histamine, 5-HT, and leukotriene C 4 in an anaphylaxis model (33,34); 2) induce increased expression of a receptor for cysteinyl leukotrienes (35); and 3) promote mast cell-dependent expulsion of Trichinella spiralis by infected mice through an effect on non-bone marrow-derived cells (24).…”

Section: Discussionmentioning

confidence: 99%

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

Madden

Whitman

Sullivan

et al. 2002

The Journal of Immunology

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152

158

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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 the sharing of a common receptor or receptor component (IL-4Rα). Binding of IL-4 by either the type 1 or 2 IL-4R, or of IL-13 by the type 2 IL-4R, initiates Jak-dependent tyrosine phosphorylation of the IL-4Rα-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, 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-hydroxytryptamine. 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 against gastrointestinal nematodes.

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“…In Strongyloides infection, intestinal mast cells are considered to be more important in enabling the host to expel the parasite, whilst in Nippostrongylus infection, goblet cells are thought to play a more significant role (Nawa et al, 1994). Furthermore, non-bone marrow-derived cells, which included intestinal epithelium, were reported to contribute to the expulsion of Nippostrongylus through increased contractility of intestine and enhanced permeability of epithelium (Urban et al, 2001). Mast cells express high affinity receptors for IgE (FcεRI) and cross-linking of IgE/FcεRI induces degranulation which contains many physiologically active molecules (Metcalfe et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Strongyloides ratti: implication of mast cell-mediated expulsion through FcεRI-independent mechanisms

et al. 2009

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Summary :In order to examine whether FcεRI-dependent degranulation of intestinal mast cells is required for expulsion of intestinal nematode Strongyloides ratti, CD45 exon6-deficient (CD45-/-) mice were inoculated with S. ratti. In CD45-/-mice, egg excretion in feces persisted for more than 30 days following S. ratti larvae inoculation, whereas in wild-type (CD45+/+) mice, the eggs completely disappeared by day 20 post-infection. The number of intestinal mucosal mast cells, which are known effector cells for the expulsion of S. ratti, was 75 % lower in CD45-/-mice compared with that in CD45+/+ mice. Adoptive transfer of wild-type T cells from CD45+/+ mice into CD45-/-mice reduced the duration of S. ratti infection to comparable levels observed in CD45+/+ mice, with concomitant increases in intestinal mucosal mast cells. These results showed that CD45 is not involved in the effector function of intestinal mucosal mast cells against S. ratti infection. Since FcεRI-dependent degranulation of mast cells is completely impaired in these CD45 knockout mice, we conclude that FcεRI-dependent degranulation is not required in the protective function of intestinal mucosal mast cells against primary infection of S. ratti. Résumé

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Cutting Edge: IL-4 Receptor Expression by Non-Bone Marrow-Derived Cells Is Required to Expel Gastrointestinal Nematode Parasites

Cited by 90 publications

References 23 publications

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

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

Strongyloides ratti: implication of mast cell-mediated expulsion through FcεRI-independent mechanisms

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