IL4R Gene Editing

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IL4R Gene Editing    

IL-4 and IL-4 Receptor

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.

IL-4 and IL-13 receptor structure.Figure 1. IL-4 and IL-13 receptor structure. (McCormick S M, Heller N M. 2015)

IL-4R Expression in Cancer

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.

IL-4Ra-Targeted 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.

IL4R Gene Editing Service

CRISPR/Cas9 PlatformCB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively IL4R gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

  • IL4R Gene Knockout: We offer IL4R gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service that covers from sgRNA design and construct, pronuclear microinjection to Founders genotyping and breeding.
  • IL4R Gene Knockin: CRISPR/Cas9 PlatformCB provides the one-stop IL4R knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of IL4R knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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References

  1. McCormick S M, Heller N M. Commentary: IL-4 and IL-13 receptors and signaling. Cytokine, 2015, 75(1): 38-50.
  2. Vogelaar C F, et al. Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation. Science translational medicine, 2018, 10(430).
  3. Ranasinghe C, Trivedi S, Wijesundara D K, et al. IL-4 and IL-13 receptors: Roles in immunity and powerful vaccine adjuvants. Cytokine & growth factor reviews, 2014, 25(4): 437-442.
  4. Suzuki A, et al. Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine, 2015, 75(1): 79-88.
For research use only. Not intended for any clinical use.

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