| Interleukin 1, alpha |
PDB rendering based on 2ila. |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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2ILA, 2KKI, 2L5X
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| Identifiers |
| Symbols |
IL1A; IL-1A; IL1; IL1-ALPHA; IL1F1 |
| External IDs |
OMIM: 147760 MGI: 96542 HomoloGene: 480 GeneCards: IL1A Gene |
| Gene Ontology |
| Molecular function |
• cytokine activity
• interleukin-1 receptor binding
• copper ion binding
• protein binding
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| Cellular component |
• extracellular region
• extracellular space
• extracellular space
• cytosol
• cell surface
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| Biological process |
• fever generation
• response to hypoxia
• apoptotic process
• anti-apoptosis
• inflammatory response
• immune response
• cell proliferation
• negative regulation of cell proliferation
• response to ozone
• response to organic nitrogen
• response to gamma radiation
• positive regulation vascular endothelial growth factor production
• positive regulation of steroid biosynthetic process
• response to organic cyclic compound
• cytokine-mediated signaling pathway
• keratinization
• response to lipopolysaccharide
• positive regulation of interleukin-6 production
• response to L-ascorbic acid
• cellular response to heat
• wound healing
• positive regulation of I-kappaB kinase/NF-kappaB cascade
• positive regulation of interleukin-2 biosynthetic process
• positive regulation of angiogenesis
• positive regulation of mitosis
• positive regulation of transcription from RNA polymerase II promoter
• positive regulation of JNK cascade
• response to copper ion
• positive regulation of cytokine secretion
• positive regulation of cell division
• regulation of sensory perception of pain
• positive regulation of ERK1 and ERK2 cascade
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
3552 |
16175 |
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| Ensembl |
ENSG00000115008 |
ENSMUSG00000027399 |
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| UniProt |
P01583 |
P01582 |
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| RefSeq (mRNA) |
NM_000575.3 |
NM_010554.4 |
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| RefSeq (protein) |
NP_000566.3 |
NP_034684.2 |
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| Location (UCSC) |
Chr 2:
113.53 – 113.54 Mb |
Chr 2:
129.13 – 129.14 Mb |
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| PubMed search |
[2] |
[3] |
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Interleukin-1 alpha (IL-1α) is a protein of the interleukin-1 family that in humans is encoded by the IL1A gene.[1][2] 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 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.[3][4] It is on the pathway that activates tumor necrosis factor-alpha.
IL-1α is a cytokine of the interleukin-1 family.
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Contents
- 1 Discovery
- 2 Alternative names
- 3 Synthesis and structure
- 4 Production and cellular sources
- 5 Interactions
- 6 Regulatory molecules
- 7 Biological activity
- 8 Applications
- 8.1 Pharmaceutical
- 8.2 Other
- 9 References
- 10 Further reading
- 11 External links
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Discovery
Interleukin 1 was discovered by Gery in 1972.[5][6][7] 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.[2]
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-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.[8] 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[9] 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.[10][11][12] 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,[13] 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,[14] 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.
Interactions
IL1A has been shown to interact with HAX1,[15] and NDN.[16]
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 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.[17]
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.[18] 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.[19]
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 collagenase secretion, induces cytoskeletal rearrangements, induces IL-6 and GCSF secretion
- induces cycloxygenase synthesis and prostaglandin PGE2 release
- causes phosphorylation of heat shock protein
- 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 infection into organism, IL-1α activates a set of immune system response processes. In particular, IL-1α:
- stimulates fibroblasts proliferation
- induces synthesis of proteases, subsequent muscle proteolysis, release of all types of amino acids in blood and stimulates acute-phase proteins synthesis
- changes the metallic ion content of blood plasma by increasing copper and decreasing zinc and iron concentration in blood
- 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,[20][21] possibly as a result of hemopoietin-1 activity.[22]
Applications
Pharmaceutical
Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals.[17] IL-1α has been administered to patients during receiving autologous bone marrow transplantation.[23] 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. There are to date no clinical trials on IL-1α as an adjuvant for tumors.
Other
IL-1α recently[when?] started to find effective application in cosmetic and dermatological formulations, which allow to significantly harmonize derma architecture.[24]
References
- ^ Nicklin MJ, Weith A, Duff GW (Jun 1994). "A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes". Genomics 19 (2): 382–4. doi:10.1006/geno.1994.1076. PMID 8188271.
- ^ a b March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, et al. (Aug 1985). "Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs". Nature 315 (6021): 641–7. doi:10.1038/315641a0. PMID 2989698.
- ^ Bankers-Fulbright JL, Kalli KR, McKean DJ (1996). "Interleukin-1 signal transduction". Life Sci. 59 (2): 61–83. doi:10.1016/0024-3205(96)00135-X. PMID 8699924.
- ^ Dinarello CA (June 1997). "Induction of interleukin-1 and interleukin-1 receptor antagonist". Semin. Oncol. 24 (3 Suppl 9): S9–81–S9–93. PMID 9208877.
- ^ I Gery, R K Gershon, and B H Waksman (1972). "Potentiation of the T-lymphocyte response to mitogens. I. The responding cell". J Exp Med 136 (1): 128–142. doi:10.1084/jem.136.1.128. PMC 2139184. PMID 5033417. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2139184.
- ^ I Gery and B H Waksman (1972). "Potentiation of the T-lymphocyte response to mitogens. II. The cellular source of potentiating mediator(s)". J Exp Med 136 (1): 143–155. doi:10.1084/jem.136.1.143.
- ^ {cite journal | author = I Gery and R E Handschumacher | title = Potentiation of the T lymphocyte response to mitogens. III. Properties of the mediator(s) from adherent cells | author = Cellular Immunology | volume = 11 | issue = 1–3 | year = 1974 | pages = 162–169 }}
- ^ Watanabe N, Kobayashi Y (November 1994). "Selective release of a processed form of interleukin 1 alpha". Cytokine 6 (6): 597–601. doi:10.1016/1043-4666(94)90046-9. PMID 7893968.
- ^ Hauser C., et al. Interleukin 1 is present in normal human epidermis. The Journal Immunology, 1986, 136, 9, 3317-23.
- ^ Gahring L.C., et al. Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum. The Journal of Clinical Investigation, 1985, 76, 4, 1585-91. [1] doi:10.1172/JCI112141
- ^ Hauser C., et al. Interleukin 1 is present in normal human epidermis. The Journal Immunology, 1986, 136, 9, 3317-23.
- ^ Schmitt A., et al. Normal epidermis contains high amounts of natural tissue IL 1 biochemical analysis by HPLC identifies a MW approximately 17 Kd form with a pH 5.7 and a MW approximately 30 Kd form. Lymphokine Research, 1986, 5, 2, 105-18.
- ^ Barland CO, Zettersten E, Brown BS, Ye J, Elias PM, Ghadially R (February 2004). "Imiquimod-induced interleukin-1 alpha stimulation improves barrier homeostasis in aged murine epidermis". J. Invest. Dermatol. 122 (2): 330–6. doi:10.1046/j.0022-202X.2004.22203.x. PMID 15009713. http://www.nature.com/jid/journal/v122/n2/pdf/5602176a.pdf.
- ^ Feldmann M, Saklatvala J (2001). "Proinflammatory cytokines". In Durum SK, Oppenheim JJ, Feldmann M. Cytokine reference: a compendium of cytokines and other mediators of host defense. Boston: Academic Press. pp. 291–306. ISBN 0-12-252673-2.
- ^ Yin H, Morioka H, Towle CA, Vidal M, Watanabe T, Weissbach L (August 2001). "Evidence that HAX-1 is an interleukin-1 alpha N-terminal binding protein". Cytokine 15 (3): 122–37. doi:10.1006/cyto.2001.0891. PMID 11554782.
- ^ Hu B, Wang S, Zhang Y, Feghali CA, Dingman JR, Wright TM (August 2003). "A nuclear target for interleukin-1alpha: interaction with the growth suppressor necdin modulates proliferation and collagen expression". Proc. Natl. Acad. Sci. U.S.A. 100 (17): 10008–13. doi:10.1073/pnas.1737765100. PMC 187743. PMID 12913118. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=187743.
- ^ a b Dinarello CA (2001). "IL-1α". In Durum SK, Oppenheim JJ, Feldmann M. Cytokine reference: a compendium of cytokines and other mediators of host defense. Boston: Academic Press. pp. 307–318. ISBN 0-12-252673-2.
- ^ Arend WP, Malyak M, Guthridge CJ, Gabay C (1998). "Interleukin-1 receptor antagonist: role in biology". Annu. Rev. Immunol. 16: 27–55. doi:10.1146/annurev.immunol.16.1.27. PMID 9597123.
- ^ Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR (1993). "Interleukin-10". Annu. Rev. Immunol. 11: 165–90. doi:10.1146/annurev.iy.11.040193.001121. PMID 8386517.
- ^ Neta R, Douches S, Oppenheim JJ (April 1986). "Interleukin 1 is a radioprotector". J. Immunol. 136 (7): 2483–5. PMID 3512714.
- ^ Dorie MJ, Allison AC, Zaghloul MS, Kallman RF (May 1989). "Interleukin 1 protects against the lethal effects of irradiation of mice but has no effect on tumors in the same animals". Proc. Soc. Exp. Biol. Med. 191 (1): 23–9. PMID 2654945.
- ^ Constine LS, Harwell S, Keng P, Lee F, Rubin P, Siemann D (March 1991). "Interleukin 1 alpha stimulates hemopoiesis but not tumor cell proliferation and protects mice from lethal total body irradiation". Int. J. Radiat. Oncol. Biol. Phys. 20 (3): 447–56. doi:10.1016/0360-3016(91)90056-A. PMID 1995530.
- ^ Smith JW, Longo DL, Alvord WG, Janik JE, Sharfman WH, Gause BL, Curti BD, Creekmore SP, Holmlund JT, Fenton RG (March 1993). "The effects of treatment with interleukin-1 alpha on platelet recovery after high-dose carboplatin". N. Engl. J. Med. 328 (11): 756–61. doi:10.1056/NEJM199303183281103. PMID 8437596.
- ^ Schoch P (2010-05-01). "Synergistic peptide action revitalises skin and hair". Personal Care Magazine. http://www.personalcaremagazine.com/Story.aspx?Story=6598.
Further reading
- Verweij CL, Bayley JP, Bakker A, Kaijzel EL (2002). "Allele specific regulation of cytokine genes: monoallelic expression of the IL-1A gene". Adv. Exp. Med. Biol.. Advances in Experimental Medicine and Biology 495: 129–39. doi:10.1007/978-1-4615-0685-0_17. ISBN 978-0-306-46656-4. PMID 11774556.
- Griffin WS, Mrak RE (2002). "Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease". J. Leukoc. Biol. 72 (2): 233–8. PMID 12149413.
- Arend WP (2003). "The balance between IL-1 and IL-1Ra in disease". Cytokine Growth Factor Rev. 13 (4–5): 323–40. doi:10.1016/S1359-6101(02)00020-5. PMID 12220547.
- Copeland KF (2006). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini reviews in medicinal chemistry 5 (12): 1093–101. doi:10.2174/138955705774933383. PMID 16375755.
- Schmidt DR, Kao WJ (2007). "The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function". Biomaterials 28 (3): 371–82. doi:10.1016/j.biomaterials.2006.08.041. PMID 16978691.
- Huynh-Ba G, Lang NP, Tonetti MS, Salvi GE (2007). "The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review". J. Clin. Periodontol. 34 (4): 305–17. doi:10.1111/j.1600-051X.2007.01055.x. PMID 17378887.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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Cell signaling: cytokines
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Chemokine
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CXCL
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CXCL1/KC · CXCL2 · CXCL3 · CXCL4 · CXCL5 · CXCL6 · CXCL7 · CXCL8/IL8 · CXCL9 · CXCL10 · CXCL11 · CXCL12 · CXCL13 · CXCL14 · CXCL15 · CXCL16 · CXCL17
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CX3CL
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CX3CL1
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XCL
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XCL1 · XCL2
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TNF
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TNFA · Lymphotoxin (TNFB/LTA, TNFC/LTB) · TNFSF4 · TNFSF5/CD40LG · TNFSF6 · TNFSF7 · TNFSF8 · TNFSF9 · TNFSF10 · TNFSF11 · TNFSF13B · EDA
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Interleukin
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Type I
(grouped by
receptor
subunit) |
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γ-chain
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IL2/IL15 · IL4/IL13 · IL7 · IL9 · IL21
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β-chain
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IL3 · IL5 · GM-CSF
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IL6 like/gp130
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IL6 · IL11 · IL27 · IL30 · IL31 (+non IL OSM, LIF, CNTF, CTF1)
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IL-12 family/IL12RB1
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IL12 · IL23 · IL27 · IL35
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Other
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IL14 · IL16 · IL32 · IL34
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Type II
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IL-10 family
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IL10/IL22 · IL19 · IL20 · IL24 · IL26 · Interferon type III (IL28/IFNL2+3 · IL29/IFNL1)
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Interferon
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I
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IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1
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II
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IFNG
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Ig superfamily
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IL-1 family: IL1A/IL1F1 · IL1B/IL1F2 · 1Ra/IL1F3 · IL1F5 · IL1F6 · IL1F7 · IL1F8 · IL1F9 · IL1F10 · 33/IL1F11 · 18/IL1G
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IL-17 family
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IL17/IL25 (IL17A)
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Other
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Hematopoietic (KITLG, Colony-stimulating factor) · SPP1
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By function/
cell |
proinflammatory cytokine (IL1, TNFA)
Monokine · Lymphokine ( Th1 (IFNG and TNFB) · Th2 (IL4, IL5, IL6, IL10, IL13) )
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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