IL21

Official Full Name

interleukin 21

Organism

Homo sapiens

GeneID

59067

Background

This gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

Synonyms

Za11; IL-21; CVID11;

Bio Chemical Class

Cytokine: interleukin

Protein Sequence

MRSSPGNMERIVICLMVIFLGTLVHKSSSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS

Open

Disease

Colorectal cancer, Diabetes mellitus

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

IL-21 has been demonstrated as a pro-inflammatory cytokine which is implicated with innate and adaptive immune responses. Thus, it has attracted much attention from researches on account of its complex structure and multi-functionality. It has been shown that IL-21 is produced mainly by CD4⁺ T cells and NKT cells, but also CD8⁺ T cells, and serves as an immune modulator via affecting various immune cells.

IL-21 and its pleiotropic functions

As illustrated in figure 1, cytokine IL-21 has diverse effects on a broad range of cell types including, but not limited to, CD4⁺ and CD8⁺ T cells, B cells, macrophages, monocytes, and dendritic cells (DCs).

Several studies have shown that the effects of IL-21 on T-cells are various including cytotoxic function, enhancement of proliferation of CD4⁺ T cells and promoting the differentiation of T_H17 and Follicular helper T cell (Tfh) cells by cooperating with IL-6. Besides, results also have shown that IL-21 stimulates proliferation of both human and mouse CD8⁺ T cells and induces production of perforin and granzymes, thus increasing their cytolytic functional capacity.

Moreover, it also has been found that a broad biological function of IL-21 on B-cells rang proliferation, differentiation from apoptosis, depending on the context of stimulation and cell type. For instance, some studies have reported that overexpression of IL-21 in murine B-cells increased the number of isotype-switched memory cells, immature transitional cells, and plasma cells, resulting in increased levels of IgG and IgM.

In addition, several studies demonstrated that IL-21 also has a capability in inducing the maturation of NK cells and enhances their cytotoxic function. Besides, some experiments have found that IL-21 is implicated with the proliferation of NKT cells, a member of T cells family that take in a series of disease processes such as autoimmunity, allergy, infection and tumor rejection. Notably, NKT cells can produce their own IL-21 after the stimulation of CD3.

Figure 1. Sources of IL-21 and its major biological actions in different immune cell types. (Leonard W J, et al.)

IL-21 and signaling pathway in immunity

Summarizing the previous studies can easily find that IL-21 performs pleiotropic biological functions via binding to the complex between the IL-21 receptor and the common cytokine-γ chain, γc，leading to the activation of downstream signaling pathways such as the Janus kinase and Signal Transducer and Activator of Transcription (JAK-STAT), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways (Figure 2). It has been shown that MAPK and PI3K pathways contribute to the proliferative effect of IL-21, modulating cell proliferation, protein translation, and survival. As for the JAK-STAT pathway, it can be further divide into STAT1, STAT3 and STAT5 pathway. Among them, STAT3 has been found plays a primary role in the biological effects of IL-21, while STAT1 also contributes to IL-21-regulated gene expression. Studies has been demonstrated that opposing actions of STAT1 and STAT3 make IL-21 various actions on a wide range of immune and non-immune cell types. However, the importance of STAT5 still need further investigation.

Additionally, reports have found that those STAT proteins form phosphorylation dimer and enter the nucleus to induce gene transcription. In T cells, it has been found that the regulation of STAT3 on genes containing AP1-IRF4 composite elements (AICEs) requires functional cooperation with interferon regulatory 4 (RF4), which binds together with basic leucine zipper transcription factor (BATF) and JUN family proteins predominately.

Figure 2. Signaling pathways activated by IL-21. (Leonard W J, et al.)

IL-21 and related diseases

Seen the pleiotropic biological functions on immunity cells mentioned above, it is easily to understand its importance in immuno-pathogenesis of several types of cancers and autoimmune diseases including Graft-versus-host disease (GVHD), Rheumatoid arthritis (RA), pemphigus and multiple sclerosis. Studies about transplant-related biology have found that IL-21/ IL-21R signaling pathways contribute to the processes of ischemia/reperfusion and acute rejection of liver or kidney transplantation. Moreover, it also has been shown that IL-21 works through signaling pathways such as JAK-STAT, MAPK and PI3K/Akt, leading to the activation of T cells, B cells, monocytes/macrophages and synovial fibroblasts in RA pathogenesis.

In general, IL-21 is an assignable cytokine in immunity diseases cause its pleiotropic biological functions on immunity cells. Thus, it is worthy to think the therapeutic potential function of IL-21 in clinical settings.

References:

Leonard W J, et al. IL-21 Signaling in Immunity. F1000research, 2016, 5(224).
Dinesh P, et al. Multifaceted role of IL‐21 in rheumatoid arthritis: Current understanding and future perspectives. Journal of Cellular Physiology, 2017, 233(282).
Ghalamfarsa G, et al. IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis. Journal of Immunotoxicology, 2015, 13(3):1-12.
Tavakolpour S. Interleukin 21 as a new possible player in pemphigus: Is it a suitable target? International Immunopharmacology, 2016, 34:139-145.
Bhatt S, et al. Interleukin 21- its potential role in the therapy of B-cell lymphomas. Leukemia & Lymphoma, 2017, 58(1):17-29.

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