Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A (Interferon lambda 1), Interleukin-28B (Interferon lambda 2), interleukin 29 (Interferon lambda 3) and interferon lambda 4. It consists of an α chain and shares a common β subunit with the

interleukin-10 receptor Interleukin-10 receptor (IL-10R) is a type II cytokine receptor. The receptor is tetrameric, composed of 2 α and 2 β subunits. The α subunit (encoded in the ''Il10ra gene)'' is expressed on haematopoietic cells (such as T, B, NK, mast, and d ...

. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

Structure

The interleukin 28 receptor consists of an interleukin-28R alpha chain (IL-28RA) and another receptor, the beta subunit of the Interleukin-10 receptor ( IL-10R2). IL-10R2 is part of the receptor for other cytokines such as IL-10, IL-22, IL-26, and IL-20. The IL-28Ra chain is a part of the cytokine receptor family 2. The IL-28Ra chain is important for recognition and ligand specificity, while the IL-10R2 is crucial in signaling.

Location

While the type 1 interferon receptor is diversely distributed, the Interleukin-28 receptor expression is more restricted, particularly the IL28RA chain. The receptor is expressed largely in epithelial cells, specifically

keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

s and melanocytes found in the epidermis. The receptor is also highly expressed in cells of the lung, kidney, intestinal tract, liver, heart and prostate. Relatively high expression has also been documented in immune cells such as dendritic cells. Other immune cell types such as Natural killer cells,

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

s and B cells, though expressing significant amounts of the IL28RA mRNA, were unresponsive to type 3 interferons. Cells such as those in the central nervous system, uterus, bone marrow, testis and skeletal muscle have low mRNA levels and do not respond to the interferon lambdas.

Function

On binding of a type 3 interferon to the IL-28RA the IL-10RB is recruited leading to the activation of two

tyrosine kinases A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

, JAK1 and

tyrosine kinase 2 Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene. Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-� ...

(tyk2). As a result STAT-1 and STAT-2 are recruited and phosphorylated. These two

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

then combine with

IRF9 Interferon regulatory factor 9 is a protein that in humans is encoded by the ''IRF9'' gene, previously known as ISGF3G. Interactions IRF9 has been shown to interact with STAT2 and STAT1 Signal transducer and activator of transcription 1 (STAT ...

to form a complex known as the interferon stimulated gene factor 3 complex (ISGF3). This enters the nucleus and binds to promoter regions, causing transcription of various genes called Interferon induced genes (ISGs) Researchers have also found that the binding of the type 3 interferons to their receptor also leads to phosphorylation of STAT-3,

STAT-4 Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind ...

, and STAT-5. In addition to the JAK/STAT pathway, other pathways such as the

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

and

PI3 kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

pathways have been discovered to be activated as a result of this ligand receptor binding. When the type 3 cytokines bind to the interleukin-28 receptor it causes several cellular responses that aid the skin cells in fighting infection. In binding to the receptor, interferon lambdas inhibit cell growth and the cell begins to produce cellular receptors that can sense infection as well as proteins to fight a viral infection. The interleukin-28 receptor, once a ligand is bound will activate a signaling pathway that causes an increase in MHC class 1 production. Once the type 3 interferons bind to their receptor, the resulting signaling cascade results in the production of IL-6, IL-8, and IL-10 by

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and monocytes. Naïve and

memory T cells Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear. Function Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...

also respond by reducing production of IL-5 and IL-13 and increasing

interferon gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheeloc ...

production. Signaling from the receptor also causes increased cytotoxicity in Natural killer cells and

Cytotoxic T cells A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...

, increased T helper cell 1 responses and MHC class 1 expression on tumor cells.

Regulation

Researchers have noted that IL-28RA gene expression is increased during stimulation by other interferons. There is also an increased expression of IL-28RA on the surface during maturation of monocytes to macrophages. While the signaling cascade induced by type 3 interferons binding to their receptor results in significant protection from infections, the response must be regulated to prevent uncontrolled inflammation and apoptosis. Mechanisms involved in regulation can include induction of suppressor of cytokine signaling proteins ( SOCSs). There also exists a soluble splice variant of the receptor that can bind the type 3 interferons thus negatively regulating signaling.

Clinical significance

Studies show that signaling of the interferon lambdas via the IL-28R reduces tumorigenicity of cancer cells and causes apoptosis.In addition, increasing expression of IL-28R increases the anticancer effects of interferon lambdas. The signaling cascade from the receptor has also been seen to reduce proliferation on human cell lines such as the BON1 pancreatic neuroendocrine tumor cell lines.Signaling through the IL-28R also protects against viruses such as encephalomyocarditis virus and vesicular stomatitis virus as well as the hepatitis B virus in hepatocytes.

References

External links

* Type II cytokine receptors {{membrane-protein-stub