Interleukin-22 receptor subunit alpha-2 (IL-22RA2), also known as interleukin-22 binding protein (IL-22BP) is a naturally secreted monomeric

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

acting as an

interleukin-22 Interleukin-22 (IL-22) is a protein that in humans is encoded by the ''IL22'' gene. Structure IL-22 is an α-helical cytokine. IL-22 binds to a heterodimeric cell surface receptor composed of IL-10R2 and IL-22R1 subunits. IL-22R is expresse ...

(IL-22)

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA i ...

, and in mice is encoded by the ''il22ra2'' gene located on chromosome 10. IL-22BP belongs to the

class II cytokine receptor Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells. They bind and respond to a select group of cytokines including interferon type I, i ...

family and it is a soluble receptor homolog of IL-22R (aliases IL-22RA1/IL-22RA/IL-22R1). The main function of IL-22BP is the regulation of IL-22 biological activity through specific binding which blocks the interaction of IL-22 with its cell surface receptor IL-22R and thus prevents the downstream

cellular signalling In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...

and response. IL-22 and IL-22BP interactions play an important role in

health Health has a variety of definitions, which have been used for different purposes over time. In general, it refers to physical and emotional well-being, especially that associated with normal functioning of the human body, absent of disease, p ...

and

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

and are involved in the regulation of steady-state

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

, inflammatory responses and

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

Structure and interaction

IL-22BP is a soluble monomeric

cytokine receptor Cytokine receptors are receptors that bind to cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly be ...

protein. IL-22BP shares approximately 34% sequence homology with the extracellular domain of one subunit of the heterodimeric membrane-bound IL-22R, which is the main cellular receptor for IL-22 providing the subsequent signalling. This homology extends to the secondary and tertiary structure of the proteins allowing specific binding and protein-protein interactions. IL-22BP also shares homology with other related cytokine receptors IL-10RB, and IL-20RA. IL-22BP is a

secreted protein A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic reti ...

that lacks both

transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...

and

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

domains, it contains two tandem fibronectin-III domains,

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

sites and four conserved

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues. The

molecular mass The molecular mass () is the mass of a given molecule, often expressed in units of daltons (Da). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The derived quan ...

of secreted IL-22BP is approximately 30 kDa. IL-22BP with its five binding loops contacts IL-22 at the site overlapping the IL-22R

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

, successfully blocking the IL-22-IL-22R interaction. The

dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (''K''D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex ...

K_D for IL-22-IL-22BP is ~ 1 pM highlighting very tight interaction and high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

, whereas K_D for IL-22-IL-22R is only ~ 20 nM meaning much lower affinity. Also, the K_off dissociation rate for the IL22BP-IL-22 complex is over 4 days but K_off dissociation rate for the IL-22R-IL-22 complex is only a few minutes. These chemical properties ensure that IL-22 which is bound to IL-22BP is effectively sequestered from interaction with IL-22R.

Function and regulation

Similarly to the expression profile of IL-22, IL-22BP is expressed in

lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lympha ...

and barrier tissues such as the

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

mesenteric lymph nodes The superior mesenteric lymph nodes may be divided into three principal groups: * mesenteric lymph nodes * ileocolic lymph nodes * mesocolic lymph nodes Structure Mesenteric lymph nodes The mesenteric lymph nodes or mesenteric glands are one of ...

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

lungs The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...

, and

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

among others. IL-22BP is produced by

dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

, particularly by specialised intestinal dendritic cell populations. Other identified cellular sources of IL-22BP include

eosinophils Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...

, CD4+ T_H lymphocytes and

keratinocytes 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 refer ...

. The detailed role of IL-22BP-IL-22 interactions is so far the best described in the gastrointestinal tract, where IL-22BP helps to maintain homeostasis and tolerance regulating IL-22 bioavailability. In the gastrointestinal tract, the levels of these two molecules are inverse during different immunological conditions. In healthy, steady-state homeostasis, the levels of IL-22BP are the highest and decrease rapidly during

immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...

and inflammation when high levels of IL-22 are produced. Inflammation mediators such as

prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnanc ...

(PGE2), IL-18 and other

inflammasome Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sens ...

components are known to downregulate IL-22BP production, on the other hand, the presence of

retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...

, metabolite of

vitamin A Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...

, is known to induce IL-22BP secretion. IL-22BP in the gut is also involved in enabling proper

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

sampling from the intestinal lumen to intestinal lymphoid tissues, which is crucial for maintaining tolerance and homeostasis. Further IL-22BP regulates

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

adsorption and

proliferation Proliferation may refer to: Weapons *Nuclear proliferation, the spread of nuclear weapons, material, and technology *Chemical weapon proliferation, the spread of chemical weapons, material, and technology *Missile proliferation, the spread of lon ...

intestinal epithelial cells The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorptio ...

. To a less extent, the function of IL-22BP is described in other tissues such as skin, lungs and liver. In most of these tissues, IL-22BP is thought to have protective effects. However, as it regulates the dual-natured IL-22 cytokine, which can have both protective and pathological effects, IL-22BP can also have both pro- and anti-inflammatory effects depending on many various conditions and stimuli. The detailed role and involvement of IL-22BP in the health and disease of different tissues remain to be fully explained.

Disease and therapy

As the function of IL-22BP implies, in general, the presence of IL-22BP has a positive/protective effect on the diseases that are exacerbated by IL-22 activity and ''vice versa''. Dysfunctional IL-22BP-IL-22 interactions have been among other molecules linked to the development inflammatory diseases of the gastrointestinal tract such as

inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...

(IBD) and its components

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

(CD) and

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

(UC). It was reported that IBD patients harbour elevated levels of both IL-22BP and IL-22 when compared to healthy controls, suggesting that in the context of chronic inflammation the effects of these molecules can be dramatically changed from the healthy state. Another research study working with ''il22ra2''

knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, ...

mouse model A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mod ...

pointed out protective role of IL-22BP in the

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

(CRC) as animals of this

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

had increased tumour formation when compared to

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...

controls. In addition to these observations, it has also been proposed that the anti-tumour effects of

lymphotoxin Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body. Lymphotoxin plays ...

α and β could be mediated in IL-22BP dependent manner. In lung infection studies with

influenza virus ''Orthomyxoviridae'' () is a family of negative-sense RNA viruses. It includes nine genera: '' Alphainfluenzavirus'', '' Betainfluenzavirus'', '' Gammainfluenzavirus'', '' Deltainfluenzavirus'', '' Isavirus'', '' Mykissvirus'', '' Quaranjavir ...

and ''

Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, hemolysis (microbiology), alpha-hemolytic member of the genus ''Streptococcus''. ''S. pneumoniae'' cells are usually found in pairs (diplococci) and do not f ...

'' the observed effects of IL-22BP were mostly negative and exacerbated infection-induced

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

due to reduced levels of active protective IL-22 on

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

tight junctions Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes between epithelial cells, sealing and preventing leakage of solutes and water. They also play a ...

and

antimicrobial peptides Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between Prokaryote, prokaryotic and eukaryota, eukaryotic cells that may ...

secretion. In mice with

experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with r ...

(EAE) which is a model of

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

(MS) negative effects of IL-22BP on the disease progression were observed, partially due to insufficient repression of pro-inflammatory

IFNγ Interferon gamma (IFNG or 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. ...

levels by neutralised IL-22. IL-22 is a target molecule for the development of novel therapies to treat chronic inflammatory diseases in which the IL-22 biological pathway is thought to be involved, such as the UC, acute

graft versus host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which remain ...

(GVHD),

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

and

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...

among others. Targeting IL-22BP biology in these therapies can also be beneficial, for example, the use of IL-22BP in a similar fashion as manufactured neutralizing

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...

against IL-22 is being studied. Novel research is pointing in the direction of using IL-22BP as a potential

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

for CRC and anti-

TNFα Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

IBD therapy prognosis.

References

External links

* {{Interleukin receptor modulators Type II cytokine receptors