IL1A
Encyclopedia
Interleukin-1 alpha is a protein
that in humans is encoded by the IL1A gene
.
The protein encoded by this gene is a cytokine
of the interleukin-1 family. Interleukin-1 alpha possesses a wide spectrum of 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
.
IL-1α is produced mainly by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis.
.
) . After processing by the removal of N-terminal amino acids by specific proteases, the resulting peptide is called "mature" form. Calpain
, a calcium-activated cysteine protease
, associated with the plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into a mature molecule. Both the 31kDa precursor form of IL-1α and its 18kDa mature form are biologically active.
The 31 kDa IL-1α precursor is synthesized in association with cytoskeletal structures (micro-tubules), unlike most proteins, which are translated in the endoplasmic reticulum.
The three-dimensional structure of the IL-1α contains an open-ended barrel composed entirely of beta-pleated strands. Crystal structure analysis of the mature form of IL-1α shows that it has two sites of binding to IL-1 receptor
. There is a primary binding site located at the open top of its barrel, which is similar, but not identical to that of IL-1β.
. The constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes interfere with the important role of IL-1α in immune responses, assuming skin
as a barrier, which prevents the entry of pathogenic microorganisms into the body.
The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age, is an additional explanation of IL-1α constitutive production in epidermis.
With the exception of skin keratinocytes, some epithelial cells and certain cells in central nervous system, the mRNA coding for IL-1α (and, thus, IL-1α itself) is not observed in health in most of cell types, tissues and in blood, in spite of wide physiological, metabolic, haematopoietic and immunological IL-1α activities.
A wide variety of other cells only upon stimulation can be induced to transcribe the IL-1α genes and produce the precursor form of IL-1α, Among them are fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils, endothelial cells, platelets, monocytes and myeloid cell lines, blood T-lymphocytes and B-lymphocytes, astrocytes, kidney mesangial cells, Langerhans cells, dermal dendritic cells, natural killer cells, large granular lymphocytes, microglia
, blood neutrophils, lymph node
cells, maternal placental cells and several other cell types.
These data allow to assume IL-1α as an epidermal cytokine.
with HAX1
, and NDN
.
Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with TNF. IL-1α and TNF are both acute phase cytokines which act to promote fever and inflammation.
There are, in fact, few examples in which the synergism between IL-1α and TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, PGE2 synthesis, sickness behavior, nitric oxide
production, nerve growth factor
synthesis, insulin
resistance, loss of mean body mass, and IL-8
and chemokine
synthesis.
into organism, IL-1α activates a set of immune system
response processes. In particular, IL-1α:
Topically administered IL-1α also stimulates expression of FGF
and EGF
, and subsequent fibroblasts and keratinocytes proliferation. This, plus the presence of large depot of IL-1α precursor in keratinocytes, suggests that locally released IL-1α may play an important role and accelerate wound healing
.
IL-1α is known to protect against lethal doses of γ-irradiation in mice, possibly as a result of hemopoietin
-1 activity.
compared with historical controls. There are to date no clinical trials on IL-1α as an adjuvant for tumors.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the IL1A gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The protein encoded by this gene is a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
of the interleukin-1 family. Interleukin-1 alpha possesses a wide spectrum of 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
Interleukin-1 receptor
Interleukin-1 receptor 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 while type II receptors may act as a suppressor of IL-1 activity by competing for...
.
IL-1α is produced mainly by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis.
Discovery
Interleukin 1 was discovered by Gery in 1972. He named it lymphocyte-activating factor (LAF) because it was a lymphocyte mitogen. It was not until 1985 that interleukin 1 was discovered to consist of two distinct proteins, now called interleukin-1 alpha and interleukin-1 betaIL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...
.
Alternative names
IL-1α is also known as fibroblast-activating factor (FAF), lymphocyte-activating factor (LAF), B-cell-activating factor (BAF), leukocyte endogenous mediator (LEM), epidermal cell-derived thymocyte-activating factor (ETAF), serum amyloid A inducer of hepatocyte-stimulating factor (HSP), catabolin, hemopoetin-1 (H-1), endogenous pyrogen (EP), osteoclast-activating factor (OAF), and proteolysis-inducing factor (PIF).Synthesis and structure
IL-1α is a unique member in the cytokine family in the sense that the structure of its initially synthesized precursor does not contain a signal peptide fragment (same is known for IL-1β and IL-18Interleukin 18
Interleukin-18 also known as IL18 is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine.- Function :...
) . After processing by the removal of N-terminal amino acids by specific proteases, the resulting peptide is called "mature" form. Calpain
Calpain
A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database...
, a calcium-activated cysteine protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
, associated with the plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into a mature molecule. Both the 31kDa precursor form of IL-1α and its 18kDa mature form are biologically active.
The 31 kDa IL-1α precursor is synthesized in association with cytoskeletal structures (micro-tubules), unlike most proteins, which are translated in the endoplasmic reticulum.
The three-dimensional structure of the IL-1α contains an open-ended barrel composed entirely of beta-pleated strands. Crystal structure analysis of the mature form of IL-1α shows that it has two sites of binding to IL-1 receptor
Interleukin-1 receptor
Interleukin-1 receptor 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 while type II receptors may act as a suppressor of IL-1 activity by competing for...
. There is a primary binding site located at the open top of its barrel, which is similar, but not identical to that of IL-1β.
Production and cellular sources
IL-1α is constitutively produced by epithelial cells. It is found in substantial amounts in normal human epidermis and is distributed in a 1:1 ratio between living epidermal cells and stratum corneumStratum corneum
The stratum corneum is the outermost layer of the epidermis, consisting of dead cells that lack nuclei and organelles. The purpose of the stratum corneum is to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress...
. The constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes interfere with the important role of IL-1α in immune responses, assuming skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
as a barrier, which prevents the entry of pathogenic microorganisms into the body.
The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age, is an additional explanation of IL-1α constitutive production in epidermis.
With the exception of skin keratinocytes, some epithelial cells and certain cells in central nervous system, the mRNA coding for IL-1α (and, thus, IL-1α itself) is not observed in health in most of cell types, tissues and in blood, in spite of wide physiological, metabolic, haematopoietic and immunological IL-1α activities.
A wide variety of other cells only upon stimulation can be induced to transcribe the IL-1α genes and produce the precursor form of IL-1α, Among them are fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils, endothelial cells, platelets, monocytes and myeloid cell lines, blood T-lymphocytes and B-lymphocytes, astrocytes, kidney mesangial cells, Langerhans cells, dermal dendritic cells, natural killer cells, large granular lymphocytes, microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
, blood neutrophils, lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
cells, maternal placental cells and several other cell types.
These data allow to assume IL-1α as an epidermal cytokine.
Interactions
IL1A has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with HAX1
HAX1
HCLS1-associated protein X-1 is a protein that in humans is encoded by the HAX1 gene.-Severe congenital neutropenia:Homozygous mutations in HAX1 are associated with autosomal recessive severe congenital neutropenia, also known as Kostmann syndrome....
, and NDN
NDN (gene)
Necdin is a protein that in humans is encoded by the NDN gene.-Interactions:NDN has been shown to interact with NUCB2, E2F1, IL1A, Low affinity nerve growth factor receptor, P53 and HNRNPU.-Further reading:...
.
Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with TNF. IL-1α and TNF are both acute phase cytokines which act to promote fever and inflammation.
There are, in fact, few examples in which the synergism between IL-1α and TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, PGE2 synthesis, sickness behavior, nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
production, nerve growth factor
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
synthesis, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
resistance, loss of mean body mass, and IL-8
IL-8
IL-8 can refer to:* Interleukin 8, a chemokine of the immune system* Illinois' 8th congressional district* Illinois Route 8...
and chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
synthesis.
Regulatory molecules
The most important regulatory molecule for IL-1α activity is IL-1Ra, which is usually produced in a 10-100-fold molar excess. In addition, the soluble form of the IL-1R type I has a high affinity for IL-1α and is produced in a 5-10 molar excess. IL-10 also inhibits IL-1α synthesis.In vitro
IL-1α possesses biological effect on cells in the picomolar to femtomolar range. In particular, IL-1α:- stimulates keratinocytes and macrophages for induced IL-1α secretion
- induces pro-collagen type I and III synthesis
- causes proliferation of fibroblasts, induces collagenase secretion, induces cytoskeletal rearrangements, induces IL-6Interleukin 6Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
and GCSF secretion - induces cycloxygenase synthesis and prostaglandinProstaglandinA prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
PGE2 release - causes phosphorylationPhosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of heat shock proteinHeat shock proteinHeat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated... - causes proliferation of smooth muscle cells, keratinocytes and stimulates release of other cytokines by keratinocytes
- induces TNFα release by endothelial cells and Ca2+ release from osteoclasts.
- stimulates hepatocytes for secretion of acute phase proteins
- induces proliferation of CD4+ cells, IL-2 production, co-stimulates CD8+/IL-1R+ cells, induces proliferation of mature B-cells and immunoglobulin secretion
- kills a limited number of tumor cells types
In vivo
Shortly after an onset of an infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
into organism, IL-1α activates a set of immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
response processes. In particular, IL-1α:
- stimulates fibroblasts proliferation
- induces synthesis of proteases, subsequent muscleMuscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
proteolysisProteolysisProteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
, release of all types of amino acids in blood and stimulates acute phase proteins synthesis - changes the metallic ion content of blood plasmaBlood plasmaBlood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
by increasing copper and decreasing zinc and iron concentration in blood - increases blood neutrophils
- activates lymphocyteLymphocyteA lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
proliferation and induces feverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
Topically administered IL-1α also stimulates expression of FGF
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
and EGF
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
, and subsequent fibroblasts and keratinocytes proliferation. This, plus the presence of large depot of IL-1α precursor in keratinocytes, suggests that locally released IL-1α may play an important role and accelerate wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
.
IL-1α is known to protect against lethal doses of γ-irradiation in mice, possibly as a result of hemopoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
-1 activity.
Pharmaceutical
Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals. IL-1α has been administered to patients during receiving autologous bone marrow transplantation. The treatment with 50 ng/kg IL-1α from day zero of autologous bone marrow or stem cells transfer resulted in an earlier recovery of thrombocytopeniaThrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
compared with historical controls. There are to date no clinical trials on IL-1α as an adjuvant for tumors.