Novel genetically-humanized mouse model established to evaluate efficacy of therapeutic agents to human interleukin-6 receptor

Ueda, Otoya; Tateishi, Hiromi; Higuchi, Y.; Fujii, Etsuko; Kato, Atsuhiko; Kawase, Yoshiaki; Wada, Naoko; Tachibe, Takanori; Kakefuda, Mami; Goto, Chisato; Kawaharada, Makoto; Shimaoka, Shin; Hattori, Kunihiro; Jishage, Kou-ichi

doi:10.1038/srep01196

Cited by 28 publications

(13 citation statements)

References 32 publications

(60 reference statements)

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“…Moreover, multiple pathogenic alterations occur in mice that express IL-6 through glial fibrillary acidic protein or neuron-specific enolase gene promoter to target glial cells or neurons, respectively [3, 5]. Humanized IL-6/IL-6 receptor system in mice has been more recently developed via the transgenic approach to demonstrate IL-6 pathology [21]. …”

Section: Introductionmentioning

confidence: 99%

Generation of a transgenic mouse line for conditional expression of human IL-6

et al. 2016

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IL-6 is a cytokine that is involved in various physiological and pathological conditions, and approaches using gain-of-function transgenic animals have contributed in elucidating IL-6 function. However, studies of the multiple functions of IL-6 in vivo are very time consuming because they require the generation of transgenic mice that harbor the gene encoding IL-6 under the control of specific promoters to mimic different pathologies. Here, we report the establishment of a conditional human IL-6 transgenic mouse, LGL-IL6, which conditionally expresses human IL-6 by taking advantage of the well-characterized Cre recombinase drivers.

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Section: Introductionmentioning

confidence: 99%

Generation of a transgenic mouse line for conditional expression of human IL-6

et al. 2016

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“…Consequently, cancer cells within PDXs have to undergo a selection process that facilitates engraftment and growth without prolactin and activation of downstream signaling mediators and target genes. Great efforts are currently being made to “humanize” ligand-receptor systems in mice as described by Ueda and colleagues for interleukin 6 (IL-6) signaling [6] or by expressing the genes coding the human variants of M-CSF, interleukin 3 (IL-3), GM-CSF, and human thrombopoietin under the control of the endogenous mouse loci [7]. …”

Section: Introductionmentioning

confidence: 99%

Mouse Models of Breast Cancer

Sakamoto

Schmidt

Wagner

2015

Methods in Molecular Biology

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Breast cancer is the most common cause of cancer death in women worldwide. This malignancy is a complex disease, which is defined by an intrinsic heterogeneity on the histopathological and molecular level as well as response to therapy and outcome. In addition to classical histopathological features, breast cancer can be categorized into at least five major subtypes based on comprehensive gene expression profiling: luminal A, luminal B, basal-like, ERBB2-positive, and normal-like breast cancer. Genetically engineered mouse models can serve as tools to study the molecular underpinnings for this disease. Given the genetic complexity that drives the initiation and progression of individual breast cancer subtypes, it is evident that certain models can reflect only particular aspects of this malignancy. In this book chapter, we will primarily focus on advances in modeling breast cancer at defined stages of carcinogenesis using genetically engineered mice. We will discuss the ability as well as shortcomings of these models to faithfully recapitulate the spectrum of human breast cancer subtypes.

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“…For example, the radioactive ligand-receptor binding test is considered to be an effective, sensitive, and classical analysis method, but safer methodologies than radiolabeled assays allow the use of radioactivity to be avoided [22] . A safe method based on the receptor-ligand binding assay mechanism is the enzyme-linked immunosorbent assay (ELISA); this is a quick, simple and extensive approach [21,23] . However, the ELISA still has room for improvement.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a novel cell-based assay for screening small molecule antagonists of human interleukin-6 receptor

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Blockade of interleukin-6 (IL-6) or its receptor (IL-6R) is effective in preventing the progression of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In the present study, we established a novel cell-based assay for identifying small molecule IL-6R antagonists. Methods: HEK293A cells were transfected with recombinant plasmids pTaglite-SNAP-IL6R and pABhFc-IL6 to obtain membranebound IL-6R and recombinant human IL-6 coupled with human Fc fragment (rhIL-6), respectively. A novel screening assay based on the interaction between IL-6R and rhIL-6 was established, optimized and validated. The stability of the assay was also assessed by calculating the Z′-factor. Results: RhIL-6 dose-dependently bound to IL-6R expressed at HEK293A cell surface. The IC 50 value of the known antagonist ab47215 was 0.38±0.08 μg/mL, which was consistent with that obtained using the traditional method (0.36±0.14 μg/mL). The value of Z′-factor was 0.68, suggesting that the novel assay was stable for high throughput screening. A total of 474 compounds were screened using the novel screening assay, and 3 compounds exhibited antagonistic activities (IC 50 =8.73±0.28, 32.32±9.08, 57.83±4.24 μg/mL). Furthermore, the active compounds dose-dependently inhibited IL-6-induced proliferation of 7TD1 cells, and reduced IL-6-induced STAT3 phosphorylation in U937 cells. Conclusion: A novel cell-based screening assay for identifying small molecule IL-6R antagonists was established, which simplifies the procedures in traditional cellular ELISA screening and profiling and reduces the costs.

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Novel genetically-humanized mouse model established to evaluate efficacy of therapeutic agents to human interleukin-6 receptor

Cited by 28 publications

References 32 publications

Generation of a transgenic mouse line for conditional expression of human IL-6

Generation of a transgenic mouse line for conditional expression of human IL-6

Mouse Models of Breast Cancer

Establishment of a novel cell-based assay for screening small molecule antagonists of human interleukin-6 receptor

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