Role of Interleukin-13 in Cancer, Pulmonary Fibrosis, and Other TH2-Type Diseases

University of Michigan, Ann Arbor, Michigan, United States
Vitamins & Hormones (Impact Factor: 2.04). 02/2006; 74:479-504. DOI: 10.1016/S0083-6729(06)74019-5
Source: PubMed


Interleukin (IL)-13 plays a major role in various inflammatory diseases including cancer, asthma, and allergy. It mediates a variety of different effects on various cell types including B cells, monocytes, natural killer cells, endothelial cells, and fibroblasts. IL-13 binds to two primary receptor chains IL-13Ralpha1 and IL-13Ralpha2. The IL-13Ralpha2 but not IL-13Ralpha1 chain binds IL-13 with high affinity and is overexpressed in a variety of human cancer cells derived from glioma, squamous cell carcinoma of head and neck, and AIDS-associated Kaposi's sarcoma. We have also demonstrated that IL-13Ralpha2 expression is greatly increased in lung cells when mice were challenged intranasally with bleomycin or Aspergillus fumigatus. In addition, IL-13Ralpha2 increased in surgical lung biopsies from patients with usual interstitial pneumonia, nonspecific interstitial pneumonia, and respiratory bronchiolitic interstitial pneumonia of unknown origin. Based on various studies, it is concluded that IL-13Ralpha2-expressing cells are involved in various pulmonary pathological conditions. In contrast, normal tissues such as brain, lung, endothelial cells, and head and neck tissues express IL-13Ralpha1 chain, but show only marginal expression of IL-13Ralpha2 chain. Thus, IL-13Ralpha2 chain may serve as a novel biomarker for diseased cells such as cancer or fibrosis and a target for receptor-directed therapeutic agents. To target IL-13R, a recombinant fusion protein composed of IL-13 and a derivative of Pseudomonas exotoxin (PE) has been produced. This cytotoxin termed as IL-13PE38QQR or IL-13PE38, or IL-13PE is highly and specifically cytotoxic to a variety of human tumor cell lines. In preclinical models of human glioblastoma, head and neck and AIDS-associated Kaposi's cancer, IL-13PE has been found to have significant antitumor activity at a tolerated dose. Several phase I clinical trials have been completed in patients with recurrent malignant glioma. Recently a phase III clinical trial (PRECISE) in patients with recurrent malignant glioma has been completed recruiting a total of 294 patients. IL-13PE cytotoxin has also shown a significant therapeutic effect in preclinical bleomycin or A. fumigatus or Schistosoma mansoni-induced pulmonary pathology including granulomatous fibrosis in mouse models. A clinical study in these diseases has yet to be initiated.

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    • "IL-13 Rα1 is expressed in healthy tissue and binds IL-13 with low affinity by itself, but when paired with IL-4α, it binds IL-13 with high affinity and forms a functional IL-13 receptor that signals and results in activation of JAK/Stat6 pathway (Hershey, 2003; Figure 1). IL-13Rα2, on the other hand, is only marginally expressed in normal tissues, but over-expressed in several abnormal conditions, including in cancer cells and during fibrosis (Jakubzick et al., 2002, 2004; Joshi et al., 2006). In contrast to its interaction with the IL-13Rα1, IL- 13 shows higher affinity binding to IL-13Rα2 which has a short cytoplasmic tail and thus is generally considered a decoy receptor in murine system as described above (Chiaramonte et al., 2003; Mentink-Kane et al., 2004; Wynn et al., 2004a). "
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    ABSTRACT: Liver fibrosis is the final common pathway of chronic liver diseases irrespective of etiology. However, etiology deeply impacts progression and characteristics of liver fibrogenesis. IL-13 is the dominant pro-fibrotic cytokine in Schistosomiasis associated liver fibrogenesis. In vitro, IL-13 directly induces expression of fibrosis-associated genes, e.g., collagens or connective tissue growth factor, in hepatic stellate cells. Recently, potential effects of IL-13 in non-Schistosomiasis associated liver fibrosis have been uncovered. This review summarizes the potential roles of IL-13 in chronic liver disease of different etiologies, and the downstream events mediating IL-13 signaling in liver fibrogenesis.
    Full-text · Article · May 2012 · Frontiers in Immunology
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    • "IL-13-PE is highly cytotoxic to tumor cells in vitro and in vivo that express high levels of IL-13Rα2 [12]. Several phase I and II clinical trials, and one phase III clinical trial, evaluating the safety, tolerability, and efficacy of this agent have been completed in patients with recurrent glioblastoma multiforme [13,14]. Most recently, we have demonstrated expression of IL-13Rα2 in human pancreatic ductal adenocarcinoma [15]. "
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    ABSTRACT: Interleukin-13 Receptor α2 (IL-13Rα2) is a tumor-associated antigen and target for cancer therapy. Since IL-13Rα2 is heterogeneously overexpressed in a variety of human cancers, it would be highly desirable to uniformly upregulate IL-13Rα2 expression in tumors for optimal targeting. We examined epigenetic regulation of IL-13Rα2 in a murine model of human pancreatic cancer by Bisulfite-PCR, sequencing for DNA methylation and chromatin immunoprecipitation for histone modification. Reverse transcription-PCR was performed for examining changes in IL-13Rα2 mRNA expression after treatment with histone deacetylase (HDAC) and c-jun inhibitors. In vitro cytotoxicity assays and in vivo testing in animal tumor models were performed to determine whether HDAC inhibitors could enhance anti-tumor effects of IL-13-PE in pancreatic cancer. Mice harboring subcutaneous tumors were treated with HDAC inhibitors systemically and IL-13-PE intratumorally. We found that CpG sites in IL-13Rα2 promoter region were not methylated in all pancreatic cancer cell lines studied including IL-13Rα2-positive and IL-13Rα2-negative cell lines and normal cells. On the other hand, histones at IL-13Rα2 promoter region were highly-acetylated in IL-13Rα2-positive but much less in receptor-negative pancreatic cancer cell lines. When cells were treated with HDAC inhibitors, not only histone acetylation but also IL-13Rα2 expression was dramatically enhanced in receptor-negative pancreatic cancer cells. In contrast, HDAC inhibition did not increase IL-13Rα2 in normal cell lines. In addition, c-jun in IL-13Rα2-positive cells was expressed at higher level than in negative cells. Two types of c-jun inhibitors prevented increase of IL-13Rα2 by HDAC inhibitors. HDAC inhibitors dramatically sensitized cancer cells to immunotoxin in the cytotoxicity assay in vitro and increased IL-13Rα2 in the tumors subcutaneously implanted in the immunodeficient animals but not in normal mice tissues. Combination therapy with HDAC inhibitors and immunotoxin synergistically inhibited growth of not only IL-13Rα2-positive but also IL-13Rα2-negative tumors. We have identified a novel function of histone modification in the regulation of IL-13Rα2 in pancreatic cancer cell lines in vitro and in vivo. HDAC inhibition provides a novel opportunity in designing combinatorial therapeutic approaches not only in combination with IL-13-PE but with other immunotoxins for therapy of pancreatic cancer and other cancers.
    Full-text · Article · Apr 2011 · Journal of Translational Medicine
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    • "Interleukin-13 (IL-13) is a natural cytokine in the body produced by activated T-helper type 2 and mast cells that inhibits the production of inflammatory cytokines in monocytes and enhances growth and differentiation of B cells, monocytes, and endothelial cells.37,77 Due to this important role in the immune system as well as its roles in allergy and cancer, IL-13 and its receptors have been extensively reviewed.16,39,130 Through investigations of the IL-13 receptor (IL-13R) composition on various cell lines, the Puri laboratory characterized its complex structure into three types (Fig. 6).37,80 "
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    ABSTRACT: Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands. Therefore, a thorough understanding of the intracellular trafficking properties of these ligands can lead to novel design criteria for engineering ligands to be more effective drug carriers. This review presents a few commonly used ligand/receptor systems where intracellular trafficking considerations can potentially improve the therapeutic efficacy of the ligand-drug molecular conjugates.
    Preview · Article · Feb 2011 · Annals of Biomedical Engineering
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