Interleukin 1-alpha

Source: Wikipedia, the free encyclopedia.
(Redirected from
IL-1α
)
Interleukin 1-alpha
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
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[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Interleukin-1 alpha (IL-1 alpha) also known as hematopoietin 1 is a

interleukin 1 family that in humans is encoded by the IL1A gene.[5][6]
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

tumor necrosis factor-alpha
.

Discovery

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 or hepatocyte-stimulating factor (HSP), catabolin, hemopoetin-1 (H-1), endogenous pyrogen (EP), 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. 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.[12] 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[13] 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

microorganisms
into the body.

The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age,[16] 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,

placental
cells and several other cell types.

IL1A is found on the surface of senescent cells, where it contributes to the production of senescence-associated secretory phenotype (SASP) factors.[18]

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

Interactions

IL1A has been shown to

interact with HAX1,[19] and NDN.[20]

Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with

PGE2 synthesis, sickness behavior, nitric oxide production, nerve growth factor synthesis, insulin resistance, loss of mean body mass, and IL-8 and chemokine synthesis.[21]

Translation of mRNA for IL1A is highly dependent upon mTOR activity.[22] IL1A and NF-κB mutually induce each other in a positive feedback loop.[23][18]

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.[24] 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.[25]

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:

  • stimulates fibroblasts proliferation
  • induces synthesis of
    acute-phase proteins
    synthesis
  • changes the metallic ion content of blood plasma by increasing copper and decreasing zinc and iron concentration in blood
  • induces production of SASP factors by senescent cells as a result of mTOR activity[22][23]
  • increases blood
    neutrophils
  • activates lymphocyte proliferation and induces 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 wound healing.

IL-1α is known to protect against lethal doses of

γ-irradiation in mice,[26][27] possibly as a result of hemopoietin-1 activity.[28]

Applications

Pharmaceutical

Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals.[21] IL-1α has been administered to patients during receiving autologous bone marrow transplantation.[29] 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.[30]

An anti-IL-1α therapeutic antibody, MABp1, is being tested in clinical trials for anti-neoplastic activity in solid tumors.[31] Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.[32]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000115008 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027399 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 8188271
    .
  6. ^ .
  7. .
  8. .
  9. .
  10. .
  11. .
  12. .
  13. ^ .
  14. .
  15. .
  16. .
  17. .
  18. ^ .
  19. .
  20. .
  21. ^ .
  22. ^ .
  23. ^ .
  24. .
  25. .
  26. .
  27. .
  28. .
  29. .
  30. .
  31. .
  32. .

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This page is based on the copyrighted Wikipedia article: IL-1α. Articles is available under the CC BY-SA 3.0 license; additional terms may apply.Privacy Policy