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: 1.78). 02/2006; 74:479-504. DOI: 10.1016/S0083-6729(06)74019-5
Source: PubMed

ABSTRACT 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.
    Frontiers in Immunology 05/2012; 3:116. DOI:10.3389/fimmu.2012.00116
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    • "Interleukin (IL)-13, a T-helper type 2 cytokine can block tumor rejection or promote tumor recurrence (Wynn, 2003) by mediate humoral immune responses (Ellyard et al., 2007), was identified by molecular cloning in activated human T lymphocytes (Murray et al., 2000), and its gene position was mapped on chromosome 5q 23–31 (Kaye et al., 2004). IL-13 is important in the generation of cell-mediated immunity (McFarlane et al., 2011) by mediates a variety of different effects on various cell types including B cells, monocytes, natural killer cells, endothelial cells, and fibroblasts (Joshi et al., 2006) and inducts B cell secreteing IgE (Murray et al., 2000). Moreover, IL-13 can inhibit tumor immunosurveillance by deviation of immune response from type 1 helper T cells to type 2 helper T cells (Wynn, 2003). "
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    ABSTRACT: Studies have shown that immune cells play a key role in lung cancer development. Five SNPs (rs1494555, rs7737000, rs20541, rs1057972 and rs2857261) are associated with lung cancer risk among Caucasians and/or African-Americans, but the polymorphisms may be implicated in different susceptibilities for lung cancer across different populations because of underlying genetic heterogeneity. We therefore conducted a study to examine this relationship in non-smoking Chinese. As a result , no significant associations were observed between SNPs and NSCLCs, whetehr of squamous cell or adenocarcinoma type. Results indicated polymorphisms of IL-7R, IL-13 and IL-15 are not major contributors to NSCLC susceptibility, although we can not rule out synergistic effects with cigarette smoke in NSCLC development in smoking Chinese.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(12):3239-44. · 2.51 Impact Factor
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    • "IL-13 is a pleiotropic cytokine that plays a key role in pulmonary pathophysiological conditions (Joshi et al., 2006a) and has recently been shown to mediate post-transplant airway fibrosis (Joshi et al., 2006a; Keane et al., 2007; Lama et al., 2006). IL-13 acts through its remodeling effects on airway epithelial cells (Laoukili et al., 2001; Relova et al., 2001; Richter et al., 2001; Zhu et al., 1999). "
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    ABSTRACT: Using an experimental model of airway fibrosis following lung transplantation, we recently showed that chronic alcohol ingestion by donor rats amplifies airway fibrosis in the recipient. Associated with alcohol-mediated amplification of airway fibrosis is increased transforming growth factor beta-1(TGFbeta(1)) and alpha-smooth muscle actin expression. Other studies have shown that interleukin-13 (IL-13) modulates TGFbeta(1) signaling during experimentally-induced airway fibrosis. Therefore, we hypothesized that IL-13 is a component of alcohol-mediated amplification of pro-fibrotic mediators in the alcoholic lung. To test this hypothesis, we analyzed tracheal epithelial cells and type II alveolar cells from control- or alcohol-fed rats, alcohol-treated mouse lung fibroblasts, and human bronchial epithelial cells in vitro for expression of various components of the IL-13 signaling pathway. Signaling via the IL-13 pathway was assessed by measuring levels of phosphorylated signal transducers and activators of transcription-6 (STAT6). In addition, we performed heterotopic tracheal transplantation using control-fed and alcohol-fed donor rats and analyzed tracheal allografts for expression of components of the IL-13 signaling pathway by RT-PCR and immunocytochemical analyses. Interleukin-13 expression was detected in type II alveolar epithelial cells and human bronchial epithelial cells, but not in lung fibroblasts. IL-13 expression was decreased in whole lung and type II cells in response to alcohol exposure. In all cell types analyzed, expression of IL-13 signaling receptor (IL-13R alpha(1)) mRNA was markedly increased. In contrast, mRNA and protein expression of the IL-13 decoy receptor (IL-13R alpha(2)) were decreased in all cells analyzed. Exposure to alcohol also increased STAT6 phosphorylation in response to IL-13 and lipopolysaccharide. Data from multiple cell types in the pulmonary system suggest that IL-13 and its receptors play a role in alcohol-mediated activation of pro-fibrotic pathways. Taken together, these data suggest that alcohol primes the airway for increased IL-13 signaling and subsequent tissue remodeling upon injury such as transplantation.
    Alcoholism Clinical and Experimental Research 03/2009; 33(3):505-13. DOI:10.1111/j.1530-0277.2008.00863.x · 3.31 Impact Factor
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Apr 24, 2015