The interleukin-1 receptor antagonist (IL-1RA) is a
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 ...
that in humans is encoded by the ''IL1RN''
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 that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
IL-1RA was initially called the IL-1 inhibitor and was discovered separately in 1984 by two independent laboratories.
IL-1RA is an agent that binds non-productively to the cell surface
interleukin-1 receptor
Interleukin-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1. Two forms of the receptor exist. The type I receptor is primarily responsible for transmitting the inflammatory effects of interleukin-1 (IL-1) while type II ...
(IL-1R), the same receptor that binds
interleukin 1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
family (IL-1), preventing IL-1's from sending a signal to that cell.
Function
IL-1RA is a member of the interleukin 1
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 ...
family. IL-1RA is secreted by various types of cells including immune cells, epithelial cells, and adipocytes, and is a natural inhibitor of the pro-inflammatory effect of IL1β.
This protein inhibits the activities of interleukin 1, alpha (
IL1A
Interleukin-1 alpha (IL-1 alpha) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the ''IL1A'' gene. In general, Interleukin 1 is responsible for the production of inflammation, as well as the ...
) and interleukin 1, beta (
IL1B
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
), and modulates a variety of interleukin 1 related immune and inflammatory responses. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. Four alternatively spliced transcript variants encoding distinct isoforms have been reported.
Clinical significance
A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures
and
gastric cancer
Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
.
Biallelic deleterious
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
in the IL1RN gene results in a rare
autoinflammatory disease
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities o ...
called
deficiency of the interleukin-1–receptor antagonist
Deficiency of the interleukin-1–receptor antagonist (DIRA) is an autosomal recessive, genetic disorder, genetic autoinflammatory syndrome resulting from mutations in ''IL1RN'', the gene encoding the interleukin 1 receptor antagonist.
Symptoms ...
(DIRA).
Variants of the IL1RN gene is also associated with risk of schizophrenia.
Elevated levels of IL-1RA has been found in serum of schizophrenia patients.
In treatment of temporomandibular joint osteoarthritis (TMJOA) the
messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
(mRNA) of IL-1RA can be used. The IL-1RA mRNA reduces pain and joint inflammation by blocking inflammatory cascade signals that lead to
osteoarthritis
Osteoarthritis is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone. A form of arthritis, it is believed to be the fourth leading cause of disability in the world, affect ...
progression.
A recombinant, slightly modified version of interleukin 1 receptor antagonist called
anakinra
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a slightly modified recombin ...
is used in the treatment of
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, an
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
disease in which IL-1 plays a key role. Anakinra differs from native human IL-1RA in that it has the addition of a single methionine residue at its amino terminus
The cytoplasmic and secreted
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of IL-1RA can suppress tumors such as
squamous cell carcinoma
Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
. The cytoplasmic isoform can protect epithelial cells from environmental factors and compete with IL1A in binding with receptors preventing activation. Then, the secreted isoform regulates IL1B in tumor microenvironments by inhibiting
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
of IL1B and proliferation of tumor cells, thus preventing the movement of tumor cells.
Use in horses
Interleukin 1 receptor antagonist is used in horses for the
treatment of equine lameness The treatment of equine lameness is a complex subject. Lameness in horses has a variety of causes, and treatment must be tailored to the type and degree of injury, as well as the financial capabilities of the owner. Treatment may be applied locally ...
secondary to joint and soft-tissue injury. IL-1RA obstructs the IL1B inflammatory cascade rather than helping to restore damaged tissue.
References
Further reading
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External links
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{{Interleukin receptor modulators
Cytokines