IL1A

Interleukin-1 alpha (IL-1α) is a is_associated_with::protein of the interleukin-1 family that in humans is encoded by the IL1A is_associated_with::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 is_associated_with::macrophages, as well as is_associated_with::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 is_associated_with::interleukin-1 receptor. It is on the pathway that activates is_associated_with::tumor necrosis factor-alpha.

IL-1α is a is_associated_with::cytokine of the interleukin-1 family.

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 beta.

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 or 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-18). After processing by the removal of N-terminal amino acids by specific proteases, the resulting peptide is called "mature" form. is_associated_with::Calpain, a calcium-activated cysteine is_associated_with::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 (microtubules), unlike most secreted proteins, which are translated on ribosomes associated with rough 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.

Production and cellular sources
IL-1α is constitutively produced by is_associated_with::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 is_associated_with::stratum corneum. The constitutive production of large amounts of IL-1α precursor by healthy epidermal is_associated_with::keratinocytes interfere with the important role of IL-1α in immune responses, assuming is_associated_with::skin as a barrier, which prevents the entry of is_associated_with::pathogenic is_associated_with::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 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 is_associated_with::fibroblasts, is_associated_with::macrophages, is_associated_with::granulocytes, is_associated_with::eosinophils, is_associated_with::mast cells and is_associated_with::basophils, is_associated_with::endothelial cells, is_associated_with::platelets, is_associated_with::monocytes and is_associated_with::myeloid cell lines, blood is_associated_with::T-lymphocytes and is_associated_with::B-lymphocytes, is_associated_with::astrocytes, kidney is_associated_with::mesangial cells, is_associated_with::Langerhans cells, dermal is_associated_with::dendritic cells, is_associated_with::natural killer cells, large granular is_associated_with::lymphocytes, is_associated_with::microglia, blood is_associated_with::neutrophils, is_associated_with::lymph node cells, maternal is_associated_with::placental cells and several other cell types.

These data allow to assume IL-1α as an epidermal cytokine.

Interactions
IL1A has been shown to interact with is_associated_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 is_associated_with::TNF. IL-1α and TNF are both acute-phase cytokines that act to promote fever and inflammation. There are, in fact, few examples in which the synergism between IL-1α and is_associated_with::TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, is_associated_with::PGE2 synthesis, sickness behavior, is_associated_with::nitric oxide production, is_associated_with::nerve growth factor synthesis, is_associated_with::insulin resistance, loss of mean body mass, and IL-8 and is_associated_with::chemokine synthesis.

Regulatory molecules
The most important regulatory molecule for IL-1α activity is IL-1Ra, which is usually produced in a 10- to 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 is_associated_with::collagenase secretion, induces is_associated_with::cytoskeletal rearrangements, induces IL-6 and is_associated_with::GCSF secretion
 * induces is_associated_with::cycloxygenase synthesis and is_associated_with::prostaglandin is_associated_with::PGE2 release
 * causes is_associated_with::phosphorylation of is_associated_with::heat shock protein
 * causes proliferation of is_associated_with::smooth muscle cells, is_associated_with::keratinocytes and stimulates release of other cytokines by keratinocytes
 * induces TNFα release by is_associated_with::endothelial cells and Ca2+ release from is_associated_with::osteoclasts.
 * stimulates hepatocytes for secretion of acute-phase proteins
 * induces proliferation of is_associated_with::CD4+ cells, IL-2 production, co-stimulates CD8+/IL-1R+ cells, induces proliferation of mature is_associated_with::B-cells and is_associated_with::immunoglobulin secretion
 * kills a limited number of is_associated_with::tumor cells types

In vivo
Shortly after an onset of an is_associated_with::infection into organism, IL-1α activates a set of is_associated_with::immune system response processes. In particular, IL-1α:
 * stimulates fibroblasts proliferation
 * induces synthesis of is_associated_with::proteases, subsequent is_associated_with::muscle is_associated_with::proteolysis, release of all types of is_associated_with::amino acids in blood and stimulates is_associated_with::acute-phase proteins synthesis
 * changes the metallic ion content of is_associated_with::blood plasma by increasing copper and decreasing zinc and iron concentration in blood
 * increases blood is_associated_with::neutrophils
 * activates is_associated_with::lymphocyte proliferation and induces is_associated_with::fever

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 is_associated_with::wound healing.

IL-1α is known to protect against lethal doses of γ-irradiation in mice,  possibly as a result of hemopoietin-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 is_associated_with::thrombocytopenia compared with historical controls. There is currently a head and neck phase III trial being run by is_associated_with::Cel-Sci Corp. involving IL-1a and many other interleukins (Multikine) as an immunotherapy. In dermatology and cosmetics topical IL-1α has been shown to increase the production of collagen and other components of the dermal matrix.