Interleukin 1-alpha
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Location (UCSC) | Chr 2: 112.77 – 112.78 Mb | Chr 2: 129.14 – 129.15 Mb | |||||||
PubMed search | [3] | [4] |
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Interleukin-1 alpha (IL-1 alpha) also known as hematopoietin 1 is a
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
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
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,
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
Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with
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
Biological activity
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 GCSFsecretion
- induces PGE2release
- causes phosphorylation of heat shock protein
- causes proliferation of keratinocytesand stimulates release of other cytokines by keratinocytes
- induces TNFα release by osteoclasts.
- stimulates hepatocytes for secretion of acute-phase proteins
- induces proliferation of immunoglobulinsecretion
- kills a limited number of tumor cellstypes
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 proteinssynthesis
- 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
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000115008 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027399 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8188271.
- ^ S2CID 4240002.
- PMID 8699924.
- PMID 9208877.
- PMID 5033417.
- PMID 5033418.
- PMID 4549027.
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- ^ S2CID 1351452.
- PMID 2997285.
- PMID 3486328.
- PMID 15009713.
- ISBN 978-0-12-252673-2.
- ^ PMID 26147250.
- PMID 11554782.
- PMID 12913118.
- ^ ISBN 978-0-12-252673-2.
- ^ S2CID 4960885.
- ^ PMID 28371119.
- PMID 9597123.
- PMID 8386517.
- S2CID 36193680.
- S2CID 7004908.
- PMID 1995530.
- S2CID 70718207.
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- PMID 25484055.
- S2CID 19860451.
Further reading
- Verweij CL, Bayley JP, Bakker A, Kaijzel EL (2002). "Allele specific regulation of cytokine genes: Monoallelic expression of the IL-lA gene". Allele specific regulation of cytokine genes: monoallelic expression of the IL-1A gene. Advances in Experimental Medicine and Biology. Vol. 495. pp. 129–39. PMID 11774556.
- Griffin WS, Mrak RE (August 2002). "Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease". Journal of Leukocyte Biology. 72 (2): 233–8. PMID 12149413.
- Arend WP (2003). "The balance between IL-1 and IL-1Ra in disease". Cytokine & Growth Factor Reviews. 13 (4–5): 323–40. PMID 12220547.
- Copeland KF (Dec 2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Reviews in Medicinal Chemistry. 5 (12): 1093–101. PMID 16375755.
- Schmidt DR, Kao WJ (January 2007). "The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function". Biomaterials. 28 (3): 371–82. PMID 16978691.
- Huynh-Ba G, Lang NP, Tonetti MS, Salvi GE (April 2007). "The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review". Journal of Clinical Periodontology. 34 (4): 305–17. PMID 17378887.
External links
- IL1A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.