Elsevier

Vitamins & Hormones

Volume 74, 2006, Pages 479-504
Vitamins & Hormones

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

https://doi.org/10.1016/S0083-6729(06)74019-5Get rights and content

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‐13Rα1 and IL‐13Rα2. The IL‐13Rα2 but not IL‐13Rα1 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‐13Rα2 expression is greatly increased in lung cells when mice were challenged intranasally with bleomycin or Aspergillus fumigatus. In addition, IL‐13Rα2 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‐13Rα2‐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‐13Rα1 chain, but show only marginal expression of IL‐13Rα2 chain. Thus, IL‐13Rα2 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.

Introduction

In this chapter, we will focus on the role of interleukin (IL)‐13 and the expression of IL‐13 receptors (IL‐13R) in various cell types including human cancer cells and different pulmonary cells. We will describe the signaling events initiated by binding of IL‐13 to its receptor. On the basis of receptor configuration present on different cell types including diseased cells, different types of receptors will be described. We will describe our observations that IL‐13Rα2 chain is upregulated in cancer and pulmonary cells by various pathological states. We will also describe that human adrenomedullin, a calcitonin‐growth‐related peptide, upregulates IL‐13Rα2 on cancer cells. The role and significance of IL‐13R in IL‐13PE cytotoxin‐mediated cytotoxicity in cancer and pulmonary diseases in vitro and in vivo will be elucidated.

Section snippets

IL‐13 and Its Receptors

IL‐13 is a 12‐kDa lymphokine that was cloned from activated T cells (Brown 1989, Minty 1993). IL‐13 protein has a 30% identity in the amino acid sequence to IL‐4 protein (de Waal Malefyt 1995, Minty 1993). IL‐13 inhibits the production of inflammatory cytokines (Aversa 1993, Minty 1993), upregulates major histocompatibility complex class II and CD23 expression on monocytes (de Waal Malefyt et al., 1993), induces anti‐CD40‐dependent IgGE class switch, and induces IgG and IgM synthesis in B cells

IL‐13R‐Mediated Signal Transduction

IL‐4R and IL‐13R systems not only share two chains (IL‐4α and IL‐13α1) with each other, both IL‐4 and IL‐13 mediate signal transduction through Janus kinase (JAK)/signal transducer and activation of transcription (STAT) pathways. Both IL‐13 and IL‐4 phosphorylate and activate JAK1 and Tyk2 tyrosine kinases in hemapoietic cells, while they phosphorylate JAK1 and JAK2 tyrosine kinases in nonhemapoietic cells such as colon carcinoma and fibroblast cells (Murata 1996, Murata 1998b). In contrast to

Effect of IL‐13 on Tumor Cells

IL‐13 inhibits cellular proliferation of three human RCC cell lines in a concentration‐dependent manner (Obiri et al., 1996). As IL‐13 binds with IL‐13Rα1 chain and recruits IL‐4Rα for signaling, we determined whether blocking IL‐4Rα by a specific antibody would inhibit IL‐13 effect. Our data demonstrated that anti‐IL‐4Rα antibody did not block the effect of IL‐13 indicating that these effects were IL‐4Rα independent (Obiri 1995, Obiri 1996). We also demonstrated that although IL‐13 did not

In Vitro Studies

The discovery of overexpression of IL‐13R on human RCC, glioma, and other tumor cell lines led us to develop an IL‐13PE cytotoxin, which is a protein product of a chimeric gene IL‐13 and mutated form of Pseudomonas exotoxin (PE) gene. The protein product is termed as IL‐13PE, IL‐13PE38, or IL‐13PE38QQR. These fusion proteins were expressed in a prokaryotic (pET) expression system using ampicillin or kanamycin as a selection antibiotic (Debinski 1995a, Joshi 2005, Joshi 2002). The recombinant

Significance of IL‐13Rα2 Expression

To study the significance of IL‐13Rα2 in cancer biology, IL‐13Rα2 gene was stably transfected into prostate, breast, and pancreatic tumor cell lines. These tumor cells were implanted subcutaneously in immunodeficient animals (Kawakami 2001a, Kawakami 2001b, Kawakami 2001c). Surprisingly, overexpression of the IL‐13Rα2 chain in these tumor cells inhibited the growth of these tumors, while mock‐transfected control tumor cells formed tumors which increased in size (Kawakami 2001a, Kawakami 2001b,

Regulation of IL‐13Rα2 Expression

The molecular mechanism of IL‐13Rα2 upregulation in humans or animals is unclear and it is known whether certain hormones, chemicals, or growth factors could act as positive or negative regulators of IL‐13Rα2 chain. In this regard, we serendipitously discovered that adrenomedullin, a calcitonin growth‐related peptide upregulates IL‐13Rα2 gene in prostate cancer cell line PC‐3 (Gonzalez‐Moreno et al., 2005). The stable transfection of adrenomedullin in this cell line resulted into over

Clinical Studies with IL‐13PE Cytotoxin

On the basis of preclinical results, several phase I/II clinical trials were initiated at various medical centers to determine safety and tolerability of IL‐13PE in patients with malignant brain tumors (Croteau 2006, Krieg 1998, Kunwar 1993, Kunwar 2003, Kunwar 2005a, Kunwar 2005b, Lang 2002, Parney 2005, Prados 2001, Prados 2002a, Prados 2002b, Prados 2005, Sampson 2004, Weingart 2001a, Weingart 2001b, Weingart 2003). In these studies, IL‐13PE cytotoxin has been administered by

IL‐13 and Chronic Lung Disease

Since its recognition as a T cell–derived factor that modulates the synthesis of inflammatory cytokines by immune cells (D'Andrea 1995, Doyle 1994), the role of IL‐13 has expanded tremendously. Although this cytokine is often grouped with other TH2‐type cytokines including IL‐4 and IL‐5, IL‐13 possesses unique qualities that distinguish it particularly from its sister cytokine IL‐4 (Zund et al., 1996). Although IL‐4 and IL‐13 share many molecular and cellular properties, IL‐13, to a greater

Activity of IL‐13PE in Pulmonary Diseases

The utility of IL‐13PE cytotoxin in targeting lung disease has been the subject of investigation in our laboratories. Unlike most other organs, drug delivery to the lung is less problematic in that it is possible to deliver drugs in an inhaled or aerosolized form. This fact has aided in examining the therapeutic effects of intranasally delivered IL‐13PE cytotoxin in experimental lung disease. The intranasal delivery of IL‐13PE cytotoxin has proved to be effective in the treatment of several

Asthma and Allergy

Concerted clinical and basic research over the past 20 years has led to the recognition that asthma is characterized by airway hyperresponsiveness, eosinophilic inflammation, mucus hypersecretion, peribronchial fibrosis, and increased IgE levels. Postmortem studies reveal that airway wall thickening (due to peribronchial fibrosis, increased muscle mass, and increased mucus producing cells) is present in asthmatic patients, and this histological observation appears to correlate to the severity

S. mansoni Granuloma Formation

Like all extracellular parasites, S. mansoni induces a strong TH2 response that culminates in profound tissue remodeling and fibrosis, particularly around the eggs released by S. mansoni. Classic granuloma responses form around tissue resident S. mansoni eggs and this pathologic process requires the actions of IL‐4 and IL‐13 (Wynn, 2003). Because receptors for IL‐4 and IL‐13 share chains, we examined the effect of IL‐13PE on the development of pulmonary granulomas in mice (Jakubzick et al., 2002

Pulmonary Fibrosis

Chronic pulmonary interstitial (or alveolar) fibrosis of known and idiopathic origin presents extraordinary clinical challenges for which treatment options show limited effectiveness (Douglas et al., 2000) or toxicity (Hampton et al., 1994), and the median survival rate following diagnosis have changed a little (Lasky 2000, Ryu 1998). At least 140 known profibrotic stimuli have been identified such as radiation, inhaled mineral and organic particles, gaseous oxidants, pharmaceutics, and

Concluding Remarks

IL‐13 has evolved as an important cytokine in inflammatory and neoplastic diseases. IL‐13 plays a major role in cancer, pulmonary asthma, pulmonary fibrosis, S. mansoni infection, ulcerative colitis, and Crohn's disease. Consistent with biological activity of IL‐13, the receptors for IL‐13 have been found to be overexpressed on a variety of diseased cell types. A majority of human tumors express type II IL‐13R, while a minority of tumors express type I IL‐13R. IL‐13Rα2 chain is uniquely

Acknowledgments

These studies were conducted as part of collaboration between the Food and Drug Administration and NeoPharm Inc. under the Cooperative Research and Development Agreement (CRADA). The views presented in this chapter do not necessarily reflect those of the Food and Drug Administration. We thank Dr. Brenton McCright of Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration for critical reading of the chapter and members of Tumor Vaccines

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    *

    Bharat H. Joshi and Cory Hogaboam contributed equally to this chapter.

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