The Interleukin-1 family (IL-1 family) is a group of 11 cytokines, which plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. In 1985 two distinct, but distantly related complementary DNAs encoding proteins sharing human IL-1 activity were reported to be isolated from a macrophage cDNA library, thus defining two individual members of the IL-1 family – IL-1α and IL-1β.
Members of IL-1 family
Table 1. IL-1 family related products
|IL-1 Ligands||IL-1 alpha / IL-1F1||IL-1 Beta / IL-1F2||IL1RN / IL-1F3|
|IL18 / IL-1F4||IL33||IL36A / IL-1F6|
|IL36B / IL-1F8||IL36G / IL-1F9||IL36RN / IL-1F5|
|IL37 / IL-1F7|
|IL1RAP / IL-1R3||IL1RAPL1 / IL-1R8||IL1RL1|
|IL1RL2 / IL-1R9||IL1R4||IL18R1|
|SIGIRR||ST2L / TMED1|
|IL-18 Binding Proteins||IL18BP|
Interleukin 1 alpha (IL-1α) 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 promotion of fever and sepsis. IL-1α inhibitors are being developed to interrupt those processes and treat diseases. IL-1α is produced mainly by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. It possesses metabolic, physiological, haematopoietic activities, and plays one of the central roles in the regulation of the immune responses. It binds to the interleukin-1 receptor. It is on the pathway that activates tumor necrosis factor-alpha. IL-1α is a “dual-function cytokine”, which means it plays a role in the nucleus by affecting transcription, apart from its extracellular receptor-mediated effects as a classical cytokine.
Figure1. IL-1α protein
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. It is a member of the interleukin 1 family of cytokines. This cytokine is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE). There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta (this gene). IL-1β precursor is cleaved by cytosolic caspase 1 (interleukin 1 beta convertase) to form mature IL-1β.
Figure2. IL-1β protein
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 (IL-1R), the same receptor that binds interleukin 1 (IL-1), preventing IL-1 from sending a signal to that cell. 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 IL-1α and IL-1β, 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.
Interleukin-18 (IL-18, also known as interferon-gamma inducing factor) is a protein which in humans is encoded by the IL-18 gene. The protein encoded by this gene is a proinflammatory cytokine. IL-18 works by binding to the interleukin-18 receptor, and together with IL-12 it induces cell-mediated immunity following infection with microbial products like lipopolysaccharide (LPS). After stimulation with IL-18, natural killer (NK) cells and certain T cells release another important cytokine called interferon-γ (IFN-γ) or type II interferon that plays an important role in activating the macrophages or other cells.
Figure3. IL-18 protein
Interleukin 36 receptor antagonist (IL-36Ra) is a member of the interleukin-36 family of cytokines. It was previously named Interleukin-1 family member 5 (IL-1F5). The protein is known to inhibit the effects of Interleukin-36 cytokines (IL-36α, IL-36β and IL-36γ) via competing with their receptor IL-36R/IL1RL2 and thereby inhibiting their proinflammatory effects. Mutations in the IL-36RN gene resulting in a decrease or production of defective IL-36RA protein have been shown to cause inflammatory skin diseases including generalised pustular psoriasis, acrodermatitis continua suppurativa Hallopeau (ACH) and acute generalized exanthematous pustulosis (AGEP).
Interleukin-36 alpha also known as interleukin-1 family member 6 (IL1F6) is a protein that in humans is encoded by the IL36A 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.
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-37 is a protein that in humans is encoded by the IL-1F7 gene. The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine can bind to, and may be a ligand for interleukin 18 receptor (IL18R1/IL-1Rrp). This cytokine also binds to interleukin 18 binding protein (IL18BP), an inhibitory binding protein of interleukin 18 (IL18), and subsequently forms a complex with IL18 receptor beta subunit, and through which it inhibits the activity of IL18. This gene along with eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Five alternatively spliced transcript variants encoding distinct isoforms have been reported.
Interleukin-1 family member 10 is a protein that in humans is encoded by the IL-1F10 gene. The protein encoded by this gene is a member of the interleukin 1 cytokine family. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. This cytokine is thought to participate in a network of interleukin 1 family members to regulate adapted and innate immune responses. Two alternatively spliced transcript variants encoding the same protein have been reported.
Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene. It is a member of the IL-1 family that potently drives production of T helper-2 (Th2)-associated cytokines (e.g., IL-4). IL33 is a ligand for ST2 (IL1RL1), an IL-1 family receptor that is highly expressed on Th2 cells, mast cells and group 2 innate lymphocytes. IL-33 is expressed by a wide variety of cell types, including fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells, and epithelial cells. IL-33 has a role in so called cytokine-induced effector cytokine production, which means that the production of effector cytokines by differentiated T helper lymphocytes is cytokine dependent and can happen without antigen stimulation by T-cell receptor of these cells.
IL-1 is intensely produced by tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is also expressed by B lymphocytes, NK cells, microglia, and epithelial cells. They form an important part of the inflammatory response of the body against infection. These cytokines increase the expression of adhesion factors on endothelial cells to enable transmigration (also called diapedesis) of immunocompetent cells, such as phagocytes, lymphocytes and others, to sites of infection.
The precursor form of IL-1α, which has both the N-terminal and C-terminal receptor interacting domains, acts as a damage-associated molecular pattern (DAMP) molecule. DAMPs, also known as alarmins, are recognized by innate immunity cells by pattern recognition receptors (PRRs) and function as danger signals for the immune system. In short, DAMPs are released from stressed cells, which undergo necrosis or pyroptosis and their intracellular components are released into extracellular space. Because of misfolding and other oxidative changes of these molecules in the context of altered pH, they are recognized by innate immunity as molecules that should not be in extracellular space. The reasons why the cell could be stressed are infection, injury, ischemia, hypoxia, acidosis and complement lysis.
IL-33 has a role in so called cytokine-induced effector cytokine production, which means that a production of effector cytokines by differentiated T helper lymphocytes is cytokine dependent and can happen without antigen stimulation by T-cell receptor of these cells. IL-33 in combination with some STAT5 activators, such as IL-2, IL-7 or TSLP, up-regulates expression of its own receptor on already differentiated Th2 lymphocytes, because naive T helper cells nor Th1 nor Th17 populations do not have ST2 receptors.
Similar functions have IL-1 to Th17 cells and IL-18 to Th 1 lymphocytes. IL-1 combined with some STAT3 activators, such as IL-6, IL-21 or IL-23, which are important for Th17 lymphocytes differentiation, have similar positive feedback in Th17 cells just like IL-33 and STAT5 activators have in Th2 cells. They highly up-regulate expression of IL-1 receptor and RORγt on the surface of stimulated Th17 lymphocytes. The effector cytokines mediated by this signalization are IL-17A, IL-4 and IL-6. IL-18 with IL-12, which is a STAT4 activator, have similar effects on Th1 cells by up-regulating expression of IL-18R1 receptor and T-bet.
Role in disease
IL-1 has a major role in neuroinflammation. During inflammation, there are increased levels of TNF and IL-1 in the brain, and their presence may cause the breakdown of the blood-brain barrier. Polymorphisms in IL-1 genes have been found to contribute to genetic susceptibility to some cancers, ankylosing spondylitis and Grave's disease.
In terms of clinical use, because of its characterization as a hematopoetic factor, IL-1 was given to patients after bone marrow transplantation to improve the engraftment. But soon it was discovered that the patients were experiencing symptoms of systemic inflammation. Pharmacological blockade of these receptors was then sought in order to relieve symptoms. The endogenous IL-1 receptor antagonist (IL-1Ra), also known as anakinra, was tried in clinical trials to lessen systemic inflammation, but did not demonstrate a statistically significant difference from placebo.
Nowadays, the blockade of IL-1 activity (especially IL-1β) is a standard therapy for patients with autoimmune diseases or lymphomas. Anakinra (IL-1Ra) is FDA-approved as a therapy for patients with rheumatoid arthritis, because it reduces symptoms and slows joint destruction of this inflammatory disease. It has also been prescribed to patients with indolent or smoldering myeloma with a high risk of progression to multiple myeloma. In combination with other medication, IL-1Ra provides a significant increase in the number of years of progression-free disease in its recipients. The benefits of this treatment are the natural structure and no toxicity or gastrointestinal disturbances.