B6-hIL6 Mice

Catalog Number: C001605

Strain Name: C57BL/6NCya-Il6em1(hIL6)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Interleukin-6 (IL-6) is a cytokine that plays a crucial role in inflammation and B cell maturation. It is primarily produced and secreted into the serum at sites of acute and chronic inflammation, inducing inflammatory responses through the interleukin-6 receptor alpha (IL-6Rα). Upon binding to IL-6Rα, IL-6 interacts with two GP130 molecules to form a hexameric complex in a 2:2:2 configuration. This receptor complex formation recruits tyrosine kinases from the Janus kinase family (JAK1, JAK2, and TYK2), which phosphorylate tyrosine sites within the intracellular domain of GP130, leading to the activation of signaling cascades. IL-6 has a broad impact on both immune and non-immune cells. In CD4+ T helper (Th) cells, IL-6 drives the differentiation of activated naïve Th cells into IL-17 and IL-22 expressing Th17 and Th22 cells, which are crucial for anti-bacterial and anti-fungal defense. Conversely, IL-6 inhibits the differentiation of CD4+ T regulatory cells, which play a key role in restraining inflammatory responses. In hepatocytes, IL-6 induces the expression of inflammation-induced acute phase proteins, including C-reactive protein (CRP) [1]. IL-6 is a pleiotropic cytokine associated with various diseases, including diabetes and systemic juvenile idiopathic arthritis. IL-6 signatures, partially based on the activity of STAT1 and STAT3, are indicators of prognosis or therapeutic response in patients with autoimmune diseases or cancer. Its role as a target in cancer immunotherapy and autoimmune diseases has attracted widespread attention [2-4].

The B6-hIL6 mouse is an Il6 gene humanized model, in which the endogenous Il6 gene sequence in mice is replaced in situ with the human IL6 gene sequence. This model can be used in researching autoimmune diseases, inflammation-related diseases, cancer, and infectious diseases. It is also useful for the development, screening, and evaluation of IL6-targeted drugs.

Strain Strategy


Figure 1. Gene editing strategy of B6-hIL6 mice. The sequences from the ATG start codon to the TAG stop codon of the endogenous mouse Il6 gene were replaced with the sequences from the ATG start codon to the TAG stop codon of the human IL6 gene.

Application

  • Research on autoimmune diseases, inflammation-related diseases, cancer, and infectious diseases;
  • Preclinical studies on the development, screening, and evaluation of IL6-targeted drugs.

 

Validation Data

1. Gene Expression Analysis


Figure 2. Gene expression analysis in bone marrow (BM), spleen, lung, and white adipose tissue from homozygous B6-hIL6 mice and wild-type (WT) mice (6 weeks old, male). RT-qPCR results revealed that human IL6 gene expression was detected in the bone marrow, spleen, lung, and white adipose tissue of homozygous B6-hIL6 mice, while no mouse Il6 gene expression was observed. Conversely, WT mice exhibited mouse Il6 gene expression but no human IL6 gene expression. These findings indicate that the bone marrow, spleen, lung, and white adipose tissue of B6-hIL6 mice successfully express the human IL6 gene (Bars represent mean ± SEM, n = 3).

 

2. Protein Expression Analysis


Figure 3. Expression of human-specific IL6 protein in the serum of wild-type (WT) and homozygous B6-hIL6 mice before and after LPS induction (5 weeks old, male). IL6 expression was induced in mice via a single intraperitoneal injection of lipopolysaccharide (LPS), and serum was collected from WT and homozygous B6-hIL6 mice 4 hours post-injection. Human IL6 expression levels were measured using a human IL6-specific ELISA kit via enzyme-linked immunosorbent assay (ELISA). Results showed that prior to induction, no IL6 expression was detected in the serum of either WT or homozygous B6-hIL6 mice. Following LPS induction, significant human IL6 protein expression was observed in the serum of homozygous B6-hIL6 mice, whereas no human IL6 protein expression was detected in WT mice. These data demonstrate that B6-hIL6 mice successfully express human IL6 protein (Bars represent mean ± SD, n = 3).

 

References
[1]Chen YH, Spencer S, Laurence A, Thaventhiran JE, Uhlig HH. Inborn errors of IL-6 family cytokine responses. Curr Opin Immunol. 2021 Oct;72:135-145.
[2]Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015 May;16(5):448-57.
[3]Weber R, Groth C, Lasser S, Arkhypov I, Petrova V, Altevogt P, Utikal J, Umansky V. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell Immunol. 2021 Jan;359:104254.
[4]Pandolfi F, Franza L, Carusi V, Altamura S, Andriollo G, Nucera E. Interleukin-6 in Rheumatoid Arthritis. Int J Mol Sci. 2020 Jul 23;21(15):5238.