Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

Wood, Nancy; Whitters, Matthew J.; Jacobson, Bruce A.; Witek, JoAnn S.; Sypek, Joseph P.; Kasaian, Marion T.; Eppihimer, Michael J.; Unger, Michelle; Tanaka, Takashi; Goldman, Samuel J.; Collins, Mary; Donaldson, Debra D.; Grusby, Michael J.

doi:10.1084/jem.20020906

Cited by 180 publications

(145 citation statements)

References 39 publications

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“…Recent data have clearly shown that a second IL-13R acts as a regulator of IL-13-induced inflammation (49,50). Soluble IL-13R␣2 binds IL-13 with high affinity, but does not provide a signal (51,52).…”

Section: Discussionmentioning

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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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%

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-deficient mice and IL-4/IL-13-double deficient mice (48) were a gift from Dr. A. McKenzie (Medical Research Council Laboratory of Molecular Biology, Cambridge, U.K.). IL-13R␣2-deficient mice (49) and Stat6-deficient mice (C.129S2-Stat6 tm1Gru/J ) (18) were a gift from M. Grusby (Harvard University, Boston, MA). IL-13/IL-13R␣2-double deficient mice were generated by breeding IL-13-and IL-13R␣2-deficient mice.…”

Section: Micementioning

confidence: 99%

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

Khodoun

Lewis²,

Yang

et al. 2007

The Journal of Immunology

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IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4Rα and sIL-13Rα2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4Rα complexes rapidly dissociate, releasing active IL-4, whereas sIL-13Rα2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13Rα2, IL-4, or sIL-4Rα. Approximately 25% of sIL-13Rα2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13Rα2 in serum increase considerably during a Th2 response. sIL-13Rα2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4Rα-dependent while the effect of IL-13 is partially IL-4Rα-independent. Inhalation of an IL-13/sIL-13Rα2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4Rα predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Rα2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.

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“…In particular, IL-13R 2 chain has a unique property of ligand internalization after binding, 36,37 which has also been identified as a soluble protein in mouse serum and urine; 38 thus, it can be a specific inhibitor of IL-13 signaling or a decoy receptor for IL-13. [39][40][41] Moreover, IL-13R 2 chain may inhibit IL-13-mediated biologic functions in tumor growth and recurrence. 26,27,42,43 To utilize the attractive properties of IL-13R 2 chain in IL-13 cytotoxin-mediated cancer therapy, we previously tried to combine the cytotoxin treatment with gene transfer of IL-13R 2 chain.…”

mentioning

confidence: 99%

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

Saitô

Murata

Watanabe

et al. 2005

Intl Journal of Cancer

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Previous studies demonstrated that IL-13Ra2 chain-overexpressing cancer cells were highly sensitive to IL-13 cytotoxin (IL13-PE38QQR) and could be targeted by cytotoxin treatment. However, the majority of human tumors do not express high levels of IL-13Ra2 chain. To expand the IL-13 cytotoxin-mediated cancer targeting therapy, we combined cytotoxin treatment with gene transfer of IL-13Ra2 chain. We constructed a recombinant adenoviral vector carrying the human IL-13Ra2 gene (Ad-IL-13Ra2), which expresses high levels of IL-13Ra2 chain on infected cells. Human cancer cell lines A549 and HOS, which originally show no IL-13Ra2 expression and little sensitivity to IL-13 cytotoxin, were effectively converted to become sensitive to this cytotoxin after Ad-IL-13Ra2 infection. The CC 50 of IL-13 cytotoxin for Ad-IL13Ra2-infected A549 cells was <10 ng/ml, whereas the CC 50 for uninfected or control vector-infected cells was >500 ng/ml. We also examined the antitumor activity of IL-13 cytotoxin in an established xenograft model of cytotoxin-resistant human lung tumor. Only a single i.t. injection of Ad-IL-13Ra2 markedly enhanced the sensitivity of established tumors to IL-13 cytotoxin treatment; furthermore, this antitumor effect was significantly sustained for more than 1 month after the last treatment with IL-13 cytotoxin. Taken together, these results suggest the combination of adenoviral vector-mediated IL-13Ra2 gene transfer and IL-13 cytotoxin administration can be an effective targeting approach for several types of IL-13 cytotoxin-resistant cancers which show no or little expression of IL-13Ra2 chain. ' 2005 Wiley-Liss, Inc.

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Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

Cited by 180 publications

References 39 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

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

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