IRAK4 Gene Editing

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IRAK4 Gene Editing    

Interleukin-1 receptor-associated kinase 4 (IRAK4) is an intracellular serine-threonine kinase belonging to the IRAK family of kinases. IRAK4 is an innate immune system target downstream of multiple signaling receptors including IL-1R, IL-18R, IL-33R and the Toll-like receptors (TLRs). The TLRs are a family of pattern recognition receptors (PRRs) that recognize a variety of bacterial and viral pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular pathogens (DAMPs). They signal through a complex cascade of adaptor proteins and kinases resulting in NF-κB activation and cytokine expression. One of the predominant adaptor proteins required for human TLR signaling is myeloid differentiation primary-response gene 88 (MyD88). When irak4 was recruited to MyD88, through an interaction with the kinase death domain, activation of IRAK4 causes the phosphorylation of IRAK1 and/or IRAK2. This affects the recruitment of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6). Subsequent signaling through kinases TAK1 to IKKα leads to the activation of NF-κB and the production of proinflammatory cytokines IL-1, IL-8, and IL-33, as well as other chemokines, including the type I IFNs. It is important to note that IRAK4 is central to all MyD88-dependent signaling, making it a promising therapeutic target for suppressing uncharacteristic and prolonged inflammatory responses that may contribute to the progression of diseases involving innate or adaptive immunity.

Schematic of IRAK4 signaling.Figure 1. Schematic of IRAK4 signaling. (Hynes Jr J, Nair S K. 2014)

IRAK4 and Autoimmune/Inflammatory Diseases

Autoimmune and inflammatory disorders are partially driven by aberrant signaling, resulting in proinflammatory cytokine production and chronic inflammation; hence, perturbation of the signaling events which are associated with IRAK4 inhibition may lead to a therapeutic benefit in treating disorders such as psoriasis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). The proinflammatory cytokine IL-1 has been observed in the synovial fluid of RA patients, and animal models have shown that treatment with IL-1 stimulates arthritic symptoms. On the contrary, when an antibody to IL-1 is used in a collagen-induced arthritis mouse model, the arthritic condition is alleviated. In further investigations, it has been shown that TLR4 antagonism decreases IL-1 secretion and prevents joint inflammation in mouse models. Recognizing that TLR4 signaling can be responsible for IL-1 production through the MyD88 pathway indicates that inhibition of IRAK4 could result in a decrease in proinflammatory cytokine production, translating to therapeutic benefits for chronic arthritic disorders. Studies have suggested that autoimmune prone MyD88-deficient mice have reduced pharmacological symptoms of SLE compared to the control animals. Numerous other autoimmune disorders including inflammatory bowel disease, Sjogren's syndrome, and Still's disease have been associated with increased TLR signaling, further substantiating IRAK4 inhibition as a practicable strategy to treat autoimmune disorders.

IRAK4 and Cancer

Recent data show that an additional potential indication for IRAK4 inhibitors is cancer. IRAK4 is proposed to play a role in lymphomas that contain a mutation in the MYD88 adaptor protein (L265P). This mutation results in a constitutively active signaling cascade that enhances the survival of the tumor cells. The role of IRAK1 and 4 in activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL) has been studied. Through IRAK1 kinase dead mutations, it was found that IRAK1 kinase activity was not required, although the kinase appears to play a structural role. A dual IRAK4/IRAK1 kinase inhibitor previously disclosed by Amgen, killed ABC DLBCL cell lines that possess the MYD88 mutation, but it did not affect cells without this mutation. A subsequent study using a highly potent and selective IRAK4 inhibitor suggested a similar effect on the growth of ABC DLBCL cell lines in vitro as well as in tumor xenografts, and this effect may be synergistic with other B cell receptor signaling blockers (SYK, BTK, PI3Kδ inhibitors). Generally, this data indicates a promising therapeutic role for inhibition of IRAK4 in treating B cell malignancies.

IRAK4 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 IRAK4 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

  • IRAK4 Gene Knockout: We offer IRAK4 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.
  • IRAK4 Gene Knockin: CRISPR/Cas9 PlatformCB provides the one-stop IRAK4 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of IRAK4 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. Hynes Jr J, Nair S K. Advances in the discovery of small-molecule IRAK4 inhibitors. Annual reports in medicinal chemistry. Academic Press, 2014, 49: 117-133.
  2. Yamamoto T, et al. Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Molecular immunology, 2014, 58(1): 66-76.
  3. Smith G F, et al. Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation. Bioorganic & Medicinal Chemistry Letters, 2017, 27(12): 2721-2726.
  4. Seganish W M. Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015). Expert opinion on therapeutic patents, 2016, 26(8): 917-932.
  5. McElroy W T. Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018). Expert Opinion on Therapeutic Patents, 2019, 29(4): 243-259.
  6. Genung N E, Guckian K M. Small molecule inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4). Progress in medicinal chemistry. Elsevier, 2017, 56: 117-163.
For research use only. Not intended for any clinical use.

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