Interleukin 1-alpha

Interleukin 1-alpha
Identifiers
AliasesIL1A, IL-1A, IL1, IL1-ALPHA, IL1F1, interleukin 1 alpha, IL-1 alpha, IL-1α
External IDsOMIM: 147760; MGI: 96542; GeneCards: IL1A
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

3552

16175

Ensembl

ENSG00000115008

ENSMUSG00000027399

UniProt

P01583

P01582

RefSeq (mRNA)

NM_000575
NM_001371554

NM_010554

RefSeq (protein)

NP_000566
NP_001358483

NP_034684

Location (UCSC)Chr 2: 112.77 – 112.78 MbChr 2: 129.14 – 129.15 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

Interleukin-1 alpha (IL-1 alpha or IL-1α) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that is encoded by the IL1A gene in humans. In general, interleukin 1 is responsible for causing inflammation, as well as promoting fever and sepsis. IL-1α inhibitors have been developed to interrupt those processes and treat diseases, although other dual-action inhibitors are currently of larger interest to the medical community.

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, and participates in the tumor necrosis factor-alpha activation pathway.

Discovery

Interleukin 1 was discovered by Igal Gery, Richard K. Gershon, and Byron H. Waksman, from the Departments of Microbiology and Pathology at Yale School of Medicine, in 1972. They 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), and proteolysis-inducing factor (PIF).

Synthesis and structure

IL-1α is an unusual member in the cytokine family due to its missing signal peptide fragment in the structure of its initially synthesized precursor. The same is observed in IL-1β and IL-18. The "mature" form of IL-1α lacks about 100 N-terminal amino acids, which are removed by proteases. 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 31 kDa precursor form of IL-1α and its 18 kDa 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 sheets. Crystal structure analysis of the mature form of IL-1α shows that it has two binding sites for the 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 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 corneum. 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.[citation needed]

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.[citation needed]

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.

IL-1α is found on the surface of senescent cells, where it contributes to the production of senescence-associated secretory phenotype (SASP) factors.

These data suggest that IL-1α is normally an epidermal cytokine.

Interactions

IL-1α has been shown to interact 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 that act to promote fever and inflammation. There are, in fact, few examples in which the synergism between IL-1α and TNF-α 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 lean body mass, and IL-8 and chemokine synthesis.

Translation of mRNA for IL-1α is highly dependent upon mTOR activity. IL-1α and NF-κB mutually induce each other in a positive feedback loop.

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.

Biological activity

in vitro

IL-1α possesses biological effect on cells in the picomolar to femtomolar range. In particular, IL-1α:

in vivo

Shortly after an onset of an infection 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.

Applications

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 thrombocytopenia compared with historical controls. IL-1α is currently being evaluated in clinical trials as a potential therapeutic in oncology indications.

An anti-IL-1α therapeutic antibody, bermekimab (MABp1), was tested in clinical trials for anti-neoplastic activity in solid tumors. Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027399 – Ensembl, May 2017
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Further reading