IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis

Fichtner‐Feigl, Stefan; Strober, Warren; Kawakami, Koji; Puri, Raj K.; Kitani, Atsushi

doi:10.1038/nm1332

Cited by 801 publications

(734 citation statements)

References 43 publications

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“…IL-13Rα2 is a membrane glycoprotein that mediates activation of the TGF-β1 promoter upon stimulation by IL-13 (or IL-4) and tumor necrosis factor (TNF)-α [34]. IL-13Rα2 has attracted significant attention as a target for glioma therapy [35] because this receptor is overexpressed by more than 80% of adult malignant gliomas but is not expressed at detectable levels in normal brain tissues or at high levels in other normal organs except the testis [36].…”

Section: Discussionmentioning

confidence: 99%

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

et al. 2008

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We investigated the protein expression of three glioma-associated antigens (GAAs) in pediatric brain stem glioma (BSG) and non-brain stem glioma (NBSG) cases with a view to their possible use in immunotherapy. Expression of EphA2, IL-13Rα2 and Survivin were studied by immunohistochemistry on paraffin-embedded tissues using a series of 15 BSG cases and 12 NBSG cases. Thirteen of 15 BSGs and all 12 NBSGs expressed at least one of GAAs; and 7 BSGs and 9 NBSGs expressed at least two of these GAAs at higher levels than non-neoplastic brain. There was no association between the tumor grade and levels of GAA expression. Although many cases demonstrated diffuse expression of GAAs throughout specimens, partial or patchy expression was noted in a small number of cases, suggesting a need for targeting multiple GAAs in immunotherapy. These results suggest that EphA2, IL-13Ralpha2 and Survivin are suitable targets for developing vaccine strategies for pediatric glioma.

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Section: Discussionmentioning

confidence: 99%

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

et al. 2008

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“…By monitoring the development of lung inflammation in IL-13 transgenic mice, Lanone and colleagues [59] demonstrated that IL-13 can induce alveolar remodeling, respiratory failure and death, and that upregulation of MMP-2, -9, -13 and -14 by IL-13 is mediated at least partially by a MMP-12-dependent pathway. Other studies also suggested that IL-13 was able to induce transforming growth factor-β1 (TGF-β1) expression in macrophages through the activation of a specific AP-1 complex variant in bleomycininduced lung fibrosis [60]. TGF-β1, that is often considered as an anti-inflammatory growth factor, inhibits cytokine-mediated induction of MMP-12 mRNA as well as protein and enzymatic activity in chondrosarcoma-derived HTB-94 cells [37].…”

Section: A C C E P T E D Article In Pressmentioning

confidence: 99%

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

Garbacki¹,

Valentin²,

Piette³

et al. 2009

Pulmonary Pharmacology & Therapeutics

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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

127

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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IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis

Cited by 801 publications

References 43 publications

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

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

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