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In recent decades, IL-4 cytokines received considerable attention as the mediators of allergy, asthma and regulators of CD4 T-helper (Th)2 immunity. IL-4 is regarded as the archetypal Th2 expressed cytokines in the Th1/Th2 paradigm, counter-regulating Th1 responses required for efficient control of many intracellular infections. IL-4 is only involved in immune function but also in pregnancy, mammary development, fetal development and lactation, as well as in higher brain functions including learning and memory. Besides, IL-4 also plays an important role in the pathogenesis of atopy, pulmonary fibrosis, asthma, and cancer.
IL-4 can bind to three different receptor chains in different configurations to create three different types of IL-4R complexes. The type I IL-4R is composed of two subunits, the IL-4Rα and the IL-2Rγ-common (γC) chain; while the type II IL-4R is composed of the IL-4Rα and the IL-13Rα1. In type III IL-4R, all three chains are present. When IL-4 binds to IL-4Ra, it recruits one of two chains (γC or IL-13Rα1), depending on the cell type, forming a heterodimer complex that initiates signal transduction. The type I IL-4R is generally present on lymphoid T and NK cells, mast cells, basophils and most mouse B cells; whereas type II IL-4R is found on non-lymphoid tumor cells. Type III IL-4R is present on TF-1, B cells and monocytes. IL-4 predominantly signals in cancer cells through the type II IL-4R complex, and phosphorylates STAT6, resulting in increased or decreased proliferation and apoptotic resistance.
Figure 1. IL-4 and IL-13 receptor structure. (McCormick S M, Heller N M. 2015)
The IL-4 receptor subunits are expressed at low levels under homeostatic conditions and are influenced by hormones, infection, cellular/oxidative stress, and inflammation. In solid tumors, high IL-4Rα expression is associated with increased cancer cell proliferation, epithelial invasion and more aggressive metastasis. Recently, Venmar et al. showed that in human breast cancer tissue and in mouse models of metastatic breast cancer, attenuating IL-4Rα expression reduced tumor survival as well as metastatic potential by blunting AKT, mTOR and ERK signaling. These findings agree with the observations of others suggesting that phospho-STAT6, downstream of IL-4 receptor engagement, regulates pro-metastatic behaviors, such as proliferation, migration and tissue invasion. In Hodgkin/Reed-Sternberg lymphoma (HL), transformed B-cells highly expressed IL-13Rα1, secreted IL-13 and showed over-phosphorylation of STAT6. In these cells, blocking IL-4Rα and inhibiting STAT6 activation increased sensitivity to chemotherapeutics. In blood/bone marrow cancers such as HL, increased IL-13Rα1 or IL-4Rα expression may serve as a biomarker for predicting how aggressive cancer, and provide a method to monitor the effectiveness of cancer therapy.
Currently, researchers have developed a chimeric recombinant fusion protein composed of circularly permuted human IL-4 and a truncated form of Pseudomonas exotoxin (PE), termed cpIL-4 cytotoxin (cpIL-4PE), to target IL-4R in cancer. They tested cpIL-4PE for its safety and efficacy in pre-clinical mouse models of human cancers, such as glioblastoma, biliary tract, pancreatic, AIDS-associated Kaposi's sarcoma and breast cancer. Intratumoral injection of cpIL-4PE in human tumors, including glioma tumors in xenograft models, has shown remarkable antitumor effects. In another method to receptor-directed anti-cancer therapy, Seto et al., and Yang et al., developed a hybrid peptide with low molecular weight, termed IL-4Rα-lytic peptide, containing a target moiety to bind to IL-4Rα and a cellular toxic lytic peptide that selectively kills cancer cells. The intratumoral administration of this peptide dramatically inhibited the tumor growth of breast, pancreatic, head and neck, and biliary tract cancers in vivo. No specific toxicity in animals was found by either intratumoral or intravenous administration. These pre-clinical studies showed that the IL-4Rα-lytic peptide might be a potent therapeutic agent to treat receptor-positive cancers.
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