The interleukin-1 receptor antagonist (IL-1RA) is a protein that in humans is encoded by the IL1RN gene. [5] [6]
IL-1RA was initially called the IL-1 inhibitor and was discovered separately in 1984 by two independent laboratories. [7] IL-1RA is an agent that binds non-productively to the cell surface interleukin-1 receptor (IL-1R), the same receptor that binds interleukin 1 family (IL-1), preventing IL-1's from sending a signal to that cell.
IL-1RA is a member of the interleukin 1 cytokine 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. [8] This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), 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. [9]
A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures [10] and gastric cancer. [11]
Biallelic deleterious mutations in the IL1RN gene results in a rare autoinflammatory disease called deficiency of the interleukin-1–receptor antagonist (DIRA). [12] Variants of the IL1RN gene is also associated with risk of schizophrenia. [13] [14] Elevated levels of IL-1RA has been found in serum of schizophrenia patients. [15]
In treatment of temporomandibular joint osteoarthritis (TMJOA) the messenger RNA (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 progression. [16]
A recombinant, slightly modified version of interleukin 1 receptor antagonist called anakinra is used in the treatment of rheumatoid arthritis, an autoimmune disease in which IL-1 plays a key role. [17] Anakinra differs from native human IL-1RA in that it has the addition of a single methionine residue at its amino terminus [18]
The cytoplasmic and secreted isoforms of IL-1RA can suppress tumors such as squamous cell carcinoma. 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 of IL1B and proliferation of tumor cells, thus preventing the movement of tumor cells. [19]
Interleukin 1 receptor antagonist is used in horses for the treatment of equine lameness secondary to joint and soft-tissue injury. IL-1RA obstructs the IL1B inflammatory cascade rather than helping to restore damaged tissue. [20]
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.
Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.
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. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.
Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.
Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.
Interleukin 32 (IL32) is proinflammatory cytokine that in humans is encoded by the IL32 gene. Interleukin 32 can be found in higher mammals but not in rodents. It is mainly expressed intracellularly and the protein has nine different isoforms, because the pre-mRNA can be alternatively spliced. The most active and studied isoform is IL-32γ. It was first reported in 2005, although the IL-32 gene was first described in 1992. It does not belong to any cytokine family because there is almost no homology with other cytokines.
Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.
Interleukin 1 receptor, type I (IL1R1) also known as CD121a, is an interleukin receptor. IL1R1 also denotes its human gene.
Interleukin 37 (IL-37), also known as Interleukin-1 family member 7 (IL-1F7), is an anti-inflammatory cytokine important for the downregulation of pro-inflammatory cytokine production as well as the suppression of tumor cell growth.
Interleukin-36 gamma previously known as interleukin-1 family member 9 (IL1F9) is a protein that in humans is encoded by the IL36G gene.
Interleukin-36 beta also known as interleukin-1 family member 8 (IL1F8) is a protein that in humans is encoded by the IL36B gene.
The interleukin-23 receptor is a type I cytokine receptor. It is encoded in human by the IL23R gene. In complex with the interleukin-12 receptor β1 subunit (IL-12Rβ1), it is activated by the cytokine interleukin 23 (IL-23). The IL23R mRNA is 2.8 kilobases in length and includes 12 exons. The translated protein contains 629 amino acids; it is a type I penetrating protein and includes a signal peptide, an N-terminal fibronectin III-like domain and an intracellular part that contains three potential tyrosine phosphorylation domains. There are 24 IL23R splice variants in mitogen-activated lymphocytes. IL23R includes some single-nucleotide polymorphisms in the region encoding the domain that binds IL-23, which may lead to differences between people in Th17 activation. There is also a variant of IL-23R that consists of just the extracellular part and is known as soluble IL-23R. This form can compete with the membrane-bound form to bind IL-23, modulating the Th17 immune response and regulation of inflammation and immune function.
The Interleukin-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.
Gene therapy for osteoarthritis is the application of gene therapy to treat osteoarthritis (OA). Unlike pharmacological treatments which are administered locally or systemically as a series of interventions, gene therapy aims to establish sustained therapeutic effect after a single, local injection.
Interleukin 17 receptor D is a protein that in humans is encoded by the IL17RD gene.
Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.
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