IL-13, IL-4Rα, and Stat6 Are Required for the Expulsion of the Gastrointestinal Nematode Parasite Nippostrongylus brasiliensis

Urban, Joseph F.; Noben-Trauth, Nancy; Donaldson, Debra D.; Madden, Kathleen B.; Morris, Suzanne C.; Collins, Mary; Finkelman, Fred D.

doi:10.1016/s1074-7613(00)80477-x

Cited by 540 publications

(526 citation statements)

References 53 publications

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“…These different findings may be attributable, at least in part, to the different mouse strains used in these studies. STAT-6 is required for both IL-4 and IL-13 signaling, and is essential for the expulsion of both T. spiralis and N. brasiliensis from the intestine (20,21). We have shown that IL-13 (and IL-4R␣), but not IL-4, is required for T. spiralis expulsion.…”

Section: Discussionmentioning

confidence: 78%

“…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). In addition, both T. muris (23) and N. brasiliensis (24) infection generate changes in mucosal tissue architecture, including villus atrophy, crypt hyperplasia, and thickening of the muscularis externa.…”

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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: 78%

mentioning

confidence: 99%

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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“…Nevertheless, IL-13 is by all accounts the most pivotal, being required for protection against most parasitic nematodes, [60][61][62][63] perhaps for its role in supporting the migration of dendritic cells that subsequently drive adaptive immunity. 64,65 IL-13 is also critical for inducing many of the expulsion mechanisms in the intestine that will be discussed further on.…”

Section: Transmissionmentioning

confidence: 99%

“…66 Furthermore, with the exception of IL-4 in the skin, 67 IL-4 appears to be dispensable for N. brasiliensis expulsion. 61,68 The redundancy between IL-4 and IL-13 likely stems from their shared usage of the IL-4Ra subunit, [69][70][71] although interestingly, IL-4Ra deficiency in T cells has no impact on worm expulsion during either T. spiralis, 72 H. polygyrus, 73 or N. brasiliensis 61,62 infections, in contrast to total IL-4Ra ablation. 63,[73][74][75] Instead, IL-4 might need to be produced rather than recognized by T cells, as it is mostly secreted by follicular helper T cells to promote IgG1 class switching of B cells.…”

Section: Transmissionmentioning

confidence: 99%

Immunity to gastrointestinal nematode infections

2018

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“…Like IL-4, IL-13 up-regulates CD23, CD71 and MHC class II expression on B cells and monocytes [32], elicits B cell proliferation and induces IgG4 and IgE production by human B cells [32], and promotes Th2 cell differentiation [33]. In addition, IL-13 plays a dominant role to IL-4 in mediating worm expulsion to Nippostrongylus brasiliensis [34], exerts protective functions both in the chronic stages of some Leishmaniasis major infections [35] and in Listeria monocytogenes infection in the context of a Th1 cytokine response [36], and acts as the key mediator in the pathogenesis of allergic asthma [37]. Studies of T. muris showing that IL-13 mediates host protection in IL-4 -/-BALB/c mice suggest an IL-4-independent role for IL-13 in resistance to T. muris [38].…”

mentioning

confidence: 99%

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

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IL-13, IL-4Rα, and Stat6 Are Required for the Expulsion of the Gastrointestinal Nematode Parasite Nippostrongylus brasiliensis

Cited by 540 publications

References 53 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

Immunity to gastrointestinal nematode infections

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

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