Interleukin 36, or IL-36, is a group of

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s in the IL-1 family with

pro-inflammatory Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', ''d ...

effects. The role of IL-36 in inflammatory diseases is under investigation. There are four members of the IL-36 family which bind to the IL-36 receptor (

IL1RL2 Interleukin-1 receptor-like 2 is a protein that in humans is encoded by the ''IL1RL2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA t ...

/IL-1Rrp2/IL-36 receptor dimer) with varying affinities.

IL36A Interleukin-36 alpha also known as interleukin-1 family member 6 (IL1F6) is a protein that in humans is encoded by the ''IL36A'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular ...

, IL36B, and

IL36G Interleukin-36 gamma previously known as interleukin-1 family member 9 (IL1F9) is a protein that in humans is encoded by the ''IL36G'' gene. Expression ''IL36G'' is well-expressed in the epithelium of the skin, gut, and lung. In the skin ''IL36 ...

are IL-36 receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s. IL36RA is an IL-36 receptor

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.NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

mitogen-activated protein kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamma ...

s, Erk1/2 and

JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...

through IL-36R/IL-1RAcP, which targets the IL-8 promotor and results in IL-6 secretion and induces various proinflammatory mediators. Binding of the IL-36R agonists to IL-1Rrp2 recruits

IL-1RAcP Interleukin-1 receptor accessory protein is a protein that in humans is encoded by the ''IL1RAP'' gene. Interleukin 1 induces synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress, by forming a complex ...

, activating the signaling pathway. IL-36Ra binds to IL-36R, preventing the recruitment of IL-1RAcP.

Function

IL-36 has been found to activate

T cell T cells (also known as T lymphocytes) are an important part 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 receptor (TCR) on their cell ...

proliferation and release of

IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...

. Before the functions of the IL-36 cytokines were determined, they were named as derivatives of IL-1F; they were renamed to their current designations in 2010. Due to their predominant expression in

epithelial tissues 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 many i ...

, IL-36 cytokines are believed to play a significant role in the pathogenesis of skin diseases, especially that of

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 ...

. IL-36 has also been linked to

psoriatic arthritis Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...

systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...

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 ...

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 ...

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 ...

, and Sjögren's syndrome. IL-36 must be cleaved at the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

to become active, probable enzymes mediating the activation could be

neutrophil granule Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

-derived

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

elastase In molecular biology, elastase is an enzyme from the class of proteases (peptidases) that break down proteins, specifically one that can break down elastin. In other words, the name only refers to the substrate specificity (i.e. what proteins i ...

, and

cathepsin G Cathepsin G is a protein that in humans is encoded by the ''CTSG'' gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsi ...

, although they may activate the cytokines differentially. IL-36 is expressed by many cells types, most predominantly

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 ...

respiratory epithelium Respiratory epithelium, or airway epithelium, is ciliated pseudostratified columnar epithelium a type of columnar epithelium found lining most of the respiratory tract as respiratory mucosa, where it serves to moisten and protect the airways ...

, various

nervous tissue Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain ...

, and

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 monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

Genes and expression

The genes encoding for the IL-36 cytokines are found on

chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost ei ...

q14.1. All three are located in a

cluster may refer to: Science and technology Astronomy * Cluster (spacecraft), constellation of four European Space Agency spacecraft * Cluster II (spacecraft), a European Space Agency mission to study the magnetosphere * Asteroid cluster, a small ...

with other members of IL-1 family and the gene order from

centromere The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fiber ...

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...

is ''IL-1A-IL-1B-IL-37-IL-36G-IL-36A-IL-36B-IL-36RN-IL1F10-IL-1RN'', and only ''IL-1A'', ''IL''-''1B'' and ''IL-36B.'' All of them probably arose from a common ancestral gene, which is most likely a primordial IL-1 receptor antagonist gene. All three genes are mainly expressed in keratinocytes, bronchial epithelium, brain tissue, and monocytes/macrophages. In the epidermis IL-36 cytokine expression is limited to granular layer keratinocytes with little to no expression in basal layer keratinocytes. IL-36Ra is constitutively expressed in keratinocytes, whereas IL-36γ expression in keratinocytes is rapidly induced after stimulation with

TNF 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 ...

or PMA (Phorbol 12-myristate 13-acetate).

Clinical significance

IL-36-alpha functions primarily in skin and demonstrates increased expression in psoriasis. In addition, decreased expression of this gene has been linked to a poor prognosis in both

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...

and

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 ...

patients. IL-36 cytokines may play a regulatory role in the pathogenesis of inflammatory disorders such as

folliculitis Folliculitis is the infection and inflammation of one or more hair follicles. The condition may occur anywhere on hair-covered skin. The rash may appear as pimples that come to white tips on the face, chest, back, arms, legs, buttocks, or head. A ...

and eosinophilic pustular folliculitis. In addition, in

acute generalized exanthematous pustulosis Acute generalized exanthematous pustulosis (AGEP; also known as pustular drug eruption and toxic pustuloderma) is a rare skin reaction that in 90% of cases is related to medication. AGEP is characterized by sudden skin eruptions that appear on ...

, IL-36 (mainly IL-36 gamma) was overexpressed in skin lesions. Studies revealed that T cells were sufficient to cause skin inflammation after ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...

'' exposure on mice, mediating the skin inflammation via IL-36-controlled, IL-17-dependent T cell responses. IL-36 is significantly involved in the pathogenesis of psoriasis leading to it being targeted therapeutically. Human psoriatic skin plaques displayed elevated IL-36beta. In addition, It was found that serum IL-36 levels are higher in patients with psoriasis vulgaris and its levels positively correlate with disease activity, suggesting that serum IL-36 levels might serve as useful

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, ...

s in patients with psoriasis.

References

{{Interleukin receptor modulators Interleukins