Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response

Chiaramonte, Mónica G.; Mentink‐Kane, Margaret M.; Jacobson, Bruce A.; Cheever, Allen W.; Whitters, Matthew J.; Goad, Mary E.P.; Wong, Anthony; Collins, Mary; Donaldson, Debra D.; Grusby, Michael J.; Wynn, Thomas A.

doi:10.1084/jem.20020903

Cited by 247 publications

(249 citation statements)

References 76 publications

(116 reference statements)

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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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“…On the other hand, IL13Ra2 does not seem to require IL-4Ra and by itself binds IL-13 with high affinity, internalizes and also mediates signal transduction. [8][9][10][11] To determine the significance of IL-13Ra2 expression', we have discovered that over-expression of IL13Ra2 increases cancer invasion and metastasis and shortens survival time of mice with human pancreatic cancer. 12 Whether this novel function of IL-13Ra2 is extendable to other human cancers is not known.…”

mentioning

confidence: 99%

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Fujisawa

Joshi

Puri

2011

Intl Journal of Cancer

125

112

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Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Ra2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Ra2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Ra2-overexpressing and IL-13Ra2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Ra2-positive cells but not in IL-13Ra2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Ra2-positive cells but not in IL-13Ra2-negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL-13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP-1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL-13Ra2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Ra2-negative tumors. Interestingly, the IL-13Ra2-positive tumor bearing mice died earlier than mice with IL-13Ra2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Ra2-positive tumor bearing mice compared to IL-13Ra2-negative tumor mice. IL-13Ra2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Ra2-negative tumors. Taken together, IL-13Ra2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Ra2 might not only directly kill primary tumors but also prevent cancer metastasis.Ovarian cancer is the fifth major cause of cancer related deaths in women. It is estimated that 21,880 women will be diagnosed and 13,850 will die of ovarian cancer in 2010. 1 Severity of the disease is determined by staging, which is based on the distance and extent of cancer spread within the pelvic and peritoneal cavity. The 5-year survival rate of ovarian cancer patients is related to the stage of the disease. 2 Therefore, novel and effective anticancer therapies are needed to prevent cancer cell spread. We have previously reported that IL13Ra2 is a biomarker of disease in ovarian cancer and targeting of this receptor with specific immunotoxin decreases tumor burden and extends survival of animals. 3 Despite its overexpression in a variety of human tumors and its characterization as a potent target for receptor directed anticancer therapy, 4-7 the biology of this receptor is highly complex and not understood completely. IL-13Ra2 is one of two receptor subunits of IL-13R complex. Another key-player of the receptor complex is IL-13Ra1, which forms a productive complex with IL-4Ra upon binding to IL-13 and mediates signal transduction. On the other hand, IL13Ra2 does not seem to require IL-4Ra and by itself binds IL-13 with high af...

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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.…”

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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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Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response

Cited by 247 publications

References 76 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

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

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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