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Ebi3

Official Full Name
Epstein-Barr virus induced 3
Background
This gene was identified by its induced expression in B lymphocytes in response Epstein-Barr virus infection. It encodes a secreted glycoprotein belonging to the hematopoietin receptor family, and heterodimerizes with a 28 kDa protein to form interleukin 27 (IL-27). IL-27 regulates T cell and inflammatory responses, in part by activating the Jak/STAT pathway of CD4+ T cells.
Synonyms
EBI3; Epstein-Barr virus induced gene 3; interleukin-27 subunit beta; IL-27B; IL-27 subunit beta; epstein-Barr virus-induced gene 3 protein homolog; EBI-3; IL-27; Epstein-Barr virus induced 3; IL27 subunit; IL35 subunit; cytokine receptor; EBV-induced gene 3 protein; epstein-Barr virus-induced gene 3 protein; IL27B; il-27rb; si:dkey-97a13.4; Il27rbeta; interleukin 27 receptor beta

The Epstein-Barr virus-induced 3 (EBI3) gene encodes a secreted single-chain glycoprotein that is a member of the hematopoietic factor receptor family. Its precursor protein consists of 229 amino acid residues and has a molecular weight of approximately 26 kD. The first 20 amino acid residues are highly hydrophobic and constitute the signal peptide. During processing, the signal peptide is removed, forming a mature EBI3 protein consisting of amino acids 21 to 229.

EBI3 is mainly expressed in lymphoid organs such as tonsils and spleen, suggesting that EBI3 is an important immune factor regulated by the immune system. EBI3 protein is also abundantly expressed in the placenta and increases with gestational time. EBI3 and P19, P28, p35, and P40 belong to the IL-12 family and have 27% homology to P40. EBI3 binds to p28 and p35 to form the cytokines IL-27 (p28, /EBI3) and IL-35 (p35 /EBI3). There are three known forms of EBI3 protein: a heterodimer with P28 is called IL-27, and p35 is a heterodimeric IL-35 and homodimer. The function of homodimers is not known.

EBI3 Figure 1. EBI3 is one of the IL-12 family members. (Ringkowski, et al. 2014)

EBI3 Function

Both the presence and expression sites of the EBI3 protein indicate that the EBI3 protein has important functions in the immune system. In the basic research on EBI3 function, EBI3 expression promotes melanoma lung metastasis, and its main mechanism is that EBI3 deletion leads to increased expression of IFN-γ in killer dendritic cells associated with CD8+ T cell responses in mouse spleen. It can be seen that EBI3 regulates tumor immune response, but the specific mechanism, especially the tumor immunosuppressive mechanism needs further clarification. As a downstream target of regulatory T cell Foxp3 transcription factor, EBI3 promotes the proliferation of regulatory T cells (Treg cells) and inhibits effector T cell function. Activation of EBI3 receptor signaling affects a range of immune cells, inhibits Th1 and Th2 functions, and inhibits cellular immune function and humoral immune function.

Existing studies have shown that EBI3 protein is expressed in a variety of tumors and tissues, affecting tumor progression, and is inseparable from a series of changes in the tumor microenvironment, especially the immune microenvironment. Chehboun et al. found that EBI3 combined with IL6 can induce the expression of chemokines in human venous endothelial cells, and EBI3 enhances IL6 function by mediating signaling pathways and possibly activating STAT3 pathways. EBI3 activates IL6 receptor function via P28 (IL30). Liang et al. found that EBI3 blockade can cause Tc cells to resist colorectal cancer tumors, and by regulating STAT3 signaling pathway, EBI3 inhibits rectal cancer Tc cell function.

EBI3 is lowly expressed in normal lymphocytes, and non-tumor tissue lymphocytes are low in the expression of EBI3 and are only found in germinal center-derived B lymphocytes, close to CD3+ T lymphocytes. EBI3 may be involved in the pathogenesis of B-cell lymphoma. The study found that EBI3 is highly expressed in transplant-associated lymphoma, follicular lymphoma, and DLBCL, but no expression of P28 is detected. This indicates that EBI3 is continuously expressed in relevant lymphoma cells, and may be an independent factor that regulates tumor immune response, thereby affecting tumor growth and metastasis, and may be a potential target for tumor diagnosis and treatment.

EBI3 and DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults. Studies have shown that the EB virus is present in patients with diffuse large B-cell lymphoma and that the patient population is found to be older and has no immunodeficiency disease. This suggests that age-related immune system deterioration may be associated with B lymphocyte proliferation disorders in EBI3-positive diffuse large B-cell lymphoma. Clonal T cells are often expressed in EBI3-positive diffuse large B-cell lymphomas.

It has been reported that EBI3-positive B-cell lymphoma usually occurs in the elderly, and aging of immune function is the main cause. Immune aging is not simply a decline in all immune functions, but a continuous remodeling process. With age, diverse B cell function is reduced, the proliferation of B cell clone in vivo. At the same time, T cells undergo specific modifications, including a reduction in the total number of T cells including helper/inducible (CD4+) and inhibitory/cytotoxic (CD8+) cells. The reduction of T cells causes the body to be in a high-risk virus-infected state, thereby activating EBVs that are latent in B cells, leading to tumorigenesis.

Lymphoma cells expressing EBI3 can also be used to identify BL and DLBCL. In a study of 503 patients with B-cell lymphoma, EBI3 expression was not found in EBV-positive or negative BL patients; EBI3 expression was over 30% in 80% of DLBCL tumor cells. Studies have shown that high expression of C-myc in BL tumor cells inhibits the expression of EBI3. High expression of C-myc and low expression of EBI3 in tumor cells of BL patients, and relatively high expression of EBI3 in DLBCL, EBI3 can be used as a marker for differential diagnosis of BL and DLBCL. Wu et al. found that EBI3 is a new prognostic indicator for the diagnosis of diffuse large B-cell lymphoma. The study found that the body is infected with EB virus, and EBI3 positive is associated with the prognosis of diffuse large B-cell lymphoma. EBI3 positivity may be a poor prognostic factor for diffuse large B-cell lymphoma. Paydas et al. demonstrate that LMP1 expression is an important prognostic indicator for DLBCL.

References:

  1. Ringkowski, S., Thomas, P. S., & Herbert, C. (2014). Interleukin-12 family cytokines and sarcoidosis. Frontiers in Pharmacology, 5(5), 233.
  2. Chehboun, S., Labrecque-Carbonneau, J., Pasquin, S., Meliani, Y., Meddah, B., & Ferlin, W., et al. (2017). Epstein-barr virus-induced gene 3 (ebi3) can mediate il-6 trans-signaling. Journal of Biological Chemistry, 292(16), jbc.M116.762021.
  3. Liang, Y., Chen, Q., Du, W., Chen, C., Li, F., & Yang, J., et al. (2016). Epstein-barr virus-induced gene 3 (ebi3) blocking leads to induce antitumor cytotoxic t lymphocyte response and suppress tumor growth in colorectal cancer by bidirectional reciprocal-regulation stat3 signaling pathway. Mediators of Inflammation, 2016, 3214105.
  4. Wu, L., Ehlin-Henriksson, B., Zhu, H., Ernberg, I., & Klein, G. (2013). Ebv counteracts il-21-induced apoptosis in an ebv-positive diffuse large b-cell lymphoma cell line. International Journal of Cancer, 133(3), 766-770.
  5. Paydas, S. (2015). Helicobacter pylori eradication in gastric diffuse large b cell lymphoma. World Journal of Gastroenterology, 21(13), 3773-3776.

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