Interleukin-21

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to >move) is the name given to a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for induction, progression, and control of T-cell-mediated cytotoxic immune responses as well as B-cell activation (antibody production). They are predominantly produced and secreted by stimulated leukocytes, monocytes, and macrophages. To date, about 358different interleukins have been clearly identified. Each cytokine of the interleukin group is nomenclatorically assigned a number for its classification (IL-1 to IL-38).

Some structurally related substances have been grouped into families. Their members often have a similar function or participate in the fine regulation of immune responses, for example, by regulating the synthesis of related interleukins.

Interleukin-21 is a cytokine with a broad pleiotropic effect that in humans is encoded by the IL-21 gene. It was discovered in 2000. The gene is located on chromosome 4. .

IL-21 is mainly produced and secreted by activated CD4+ T cells (T helper cells), but not by CD8+ T cells. Furthermore, interleukin-21 is produced by activated NK cells, as well as by cells of Hodgkin's lymphoma.

When interleukin-21 binds to its receptor, it leads to activation of Janus kinases 1 and 3 (JAK 1 and JAK 3) and the signal transducer and activator of transcription (STAT 1 and STAT3) pathway. Furthermore, interleukin-21 activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK) pathways.

Interleukin-21 is thus an important regulator of T cell functions. Interleukin -21 enhances proliferation of anti-CD3-stimulated T cells and co-acts with other cytokines in inducing growth of CD4+ and, together with interleukins 7 and 15, CD8+ T cells.

In addition to its influence on the regulation of T cells, the cytokine affects proliferation and maturation of B cells as well as antibody induction. It plays an important role in the differentiation of B cells into plasma cells.

Interleukin-21 is involved in the modulation and activation of so-called T follicular helper cells (TFH cells).

IL-21 plays a dominant role in the control of allergic reactions, through its role in IgE-mediated immune response. Interleukin-21 is able to attenuate allergic reactions by reducing T-cell induced proinflammatory cytokines.

It is believed that interleukin-21 is an important factor in the control and defence of viral infections. In animal experiments, a targeted suppression of CD4-induced interleukin-21 formation leads to a persistence of viral infections. Thus, IL-21-stimulated CD8 or NK cells are able to inhibit the viral replication of HIV in vitro. This approach may open a therapeutic window for interleukin-21-associated anti-HIV therapy.

In summary, IL-21 modulates both innate and adaptive immunity processes and functions, especially those involved in the processing of autoimmune and inflammatory infectious and non-infectious diseases. Furthermore, the cytokine plays an important role in immunological antitumor reactions.

Numerous studies with suppressive or activating approaches on interleukin-21 functions, have been inaugurated in different diseases. IL-21 has been used clinically (phase 1 and 2 studies) in patients with metastatic melanoma and renal cell carcinoma.

IL-21 plays a dominant role in the control of allergic reactions, through its function in the IgE mediated -immune response. Interleukin- 21 is able to attenuate allergic reactions by reducing T-cell-induced proinflammatory cytokines.

It is further suggested that interleukin-21 plays an important role in the control and defense against viral infections. In animal experiments, targeted suppression of CD4-induced interleukin-21 formation leads to persistence of viral infections.

Conversely, IL-21-stimulated CD8 or NK cells are able to suppress viral replication of HIV in vitro. This approach potentially opens a therapeutic window for interleukin-21-associated anti-HIV therapy.

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