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Interleukin 1-alpha

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Interleukin 1-alpha
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesIL1A,IL-1A, IL1, IL1-ALPHA, IL1F1, interleukin 1 alpha, IL-1 alpha, IL-1α
External IDsOMIM:147760;MGI:96542;HomoloGene:480;GeneCards:IL1A;OMA:IL1A - orthologs
Orthologs
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
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Interleukin-1 alpha(IL-1 alpha) also known ashematopoietin 1is acytokineof theinterleukin 1 familythat in humans is encoded by theIL1Agene.[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 activatedmacrophages,as well asneutrophils,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 theinterleukin-1 receptor.[7][8]It is on the pathway that activatestumor necrosis factor-alpha.

Discovery[edit]

Interleukin 1 was discovered by Gery in 1972.[9][10][11]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 andinterleukin-1 beta.[6]

Alternative names[edit]

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[edit]

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 andIL-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 cysteineprotease,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 toIL-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[edit]

IL-1α is constitutively produced byepithelial cells.It is found in substantial amounts in normal humanepidermisand is distributed in a 1:1 ratio between living epidermal cells andstratum corneum.[13][14][15]The constitutive production of large amounts of IL-1α precursor by healthy epidermalkeratinocytesinterfere with the important role of IL-1α in immune responses, assumingskinas a barrier, which prevents the entry ofpathogenicmicroorganismsinto 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,[17]Among them arefibroblasts,macrophages,granulocytes,eosinophils,mast cellsandbasophils,endothelial cells,platelets,monocytesandmyeloid celllines, bloodT-lymphocytesandB-lymphocytes,astrocytes,kidneymesangial cells,Langerhans cells,dermaldendritic cells,natural killer cells,large granularlymphocytes,microglia,bloodneutrophils,lymph nodecells, maternalplacentalcells and several other cell types.

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

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

Interactions[edit]

IL1A has been shown tointeractwithHAX1,[19]andNDN.[20]

Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism withTNF.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 andTNFαhas not been demonstrated. These include radioprotection, the Shwartzman reaction,PGE2synthesis, sickness behavior,nitric oxideproduction,nerve growth factorsynthesis,insulinresistance, loss of mean body mass, andIL-8andchemokinesynthesis.[21]

Translation ofmRNAfor IL1A is highly dependent uponmTORactivity.[22]IL1A andNF-κBmutually induce each other in apositive feedback loop.[23][18]

Regulatory molecules[edit]

The most important regulatory molecule for IL-1α activity isIL-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-10also inhibits IL-1α synthesis.[25]

Biological activity[edit]

In vitro[edit]

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

In vivo[edit]

Shortly after an onset of aninfectioninto organism, IL-1α activates a set ofimmune systemresponse processes. In particular, IL-1α:

Topically administered IL-1α also stimulates expression ofFGFandEGF,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 acceleratewound healing.

IL-1α is known to protect against lethal doses ofγ-irradiationin mice,[26][27]possibly as a result ofhemopoietin-1 activity.[28]

Applications[edit]

Pharmaceutical[edit]

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 ofthrombocytopeniacompared 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[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000115008–Ensembl,May 2017
  2. ^abcGRCm38: 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. ^Nicklin MJ, Weith A, Duff GW (Jan 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.PMID8188271.
  6. ^abMarch CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K (August 1985). "Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs".Nature.315(6021): 641–7.Bibcode:1985Natur.315..641M.doi:10.1038/315641a0.PMID2989698.S2CID4240002.
  7. ^Bankers-Fulbright JL, Kalli KR, McKean DJ (1996). "Interleukin-1 signal transduction".Life Sciences.59(2): 61–83.doi:10.1016/0024-3205(96)00135-X.PMID8699924.
  8. ^Dinarello CA (June 1997). "Induction of interleukin-1 and interleukin-1 receptor antagonist".Seminars in Oncology.24(3 Suppl 9): S9–81–S9–93.PMID9208877.
  9. ^Gery I, Gershon RK, Waksman BH (Jul 1972)."Potentiation of the T-lymphocyte response to mitogens. I. The responding cell".The Journal of Experimental Medicine.136(1): 128–42.doi:10.1084/jem.136.1.128.PMC2139184.PMID5033417.
  10. ^Gery I, Waksman BH (Jul 1972)."Potentiation of the T-lymphocyte response to mitogens. II. The cellular source of potentiating mediator(s)".The Journal of Experimental Medicine.136(1): 143–55.doi:10.1084/jem.136.1.143.PMC2139186.PMID5033418.
  11. ^Gery I, Handschumacher RE (March 1974). "Potentiation of the T lymphocyte response to mitogens. III. Properties of the mediator(s) from adherent cells".Cellular Immunology.11(1–3): 162–9.doi:10.1016/0008-8749(74)90016-1.PMID4549027.
  12. ^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.PMID7893968.
  13. ^abHauser C, Saurat JH, Schmitt A, Jaunin F, Dayer JM (May 1986)."Interleukin 1 is present in normal human epidermis".Journal of Immunology.136(9): 3317–23.doi:10.4049/jimmunol.136.9.3317.PMID3007615.S2CID1351452.
  14. ^Gahring LC, Buckley A, Daynes RA (Oct 1985)."Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum".The Journal of Clinical Investigation.76(4): 1585–91.doi:10.1172/JCI112141.PMC424137.PMID2997285.
  15. ^Schmitt A, Hauser C, Jaunin F, Dayer JM, Saurat JH (1986). "Normal epidermis contains high amounts of natural tissue IL 1 biochemical analysis by HPLC identifies a MW approximately 17 Kd form with a P1 5.7 and a MW approximately 30 Kd form".Lymphokine Research.5(2): 105–18.PMID3486328.
  16. ^Barland CO, Zettersten E, Brown BS, Ye J, Elias PM, Ghadially R (Feb 2004)."Imiquimod-induced interleukin-1 alpha stimulation improves barrier homeostasis in aged murine epidermis"(PDF).The Journal of Investigative Dermatology.122(2): 330–6.doi:10.1046/j.0022-202X.2004.22203.x.PMID15009713.
  17. ^Feldmann M, Saklatvala J (2001). "Proinflammatory cytokines". In Durum SK, Oppenheim JJ, Feldmann M (eds.).Cytokine reference: a compendium of cytokines and other mediators of host defense.Boston: Academic Press. pp. 291–306.ISBN978-0-12-252673-2.
  18. ^abLaberge R, Sun Y, Orjalo AV, Patil CK, Campisi J (2015)."MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation".Nature Cell Biology.17(8): 1049–1061.doi:10.1038/ncb3195.PMC4691706.PMID26147250.
  19. ^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.PMID11554782.
  20. ^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".Proceedings of the National Academy of Sciences of the United States of America.100(17): 10008–13.Bibcode:2003PNAS..10010008H.doi:10.1073/pnas.1737765100.PMC187743.PMID12913118.
  21. ^abDinarello CA (2001). "IL-1α". In Durum SK, Oppenheim JJ, Feldmann M (eds.).Cytokine reference: a compendium of cytokines and other mediators of host defense.Boston: Academic Press. pp. 307–318.ISBN978-0-12-252673-2.
  22. ^abWang R, Sunchu B, Perez VI (2017). "Rapamycin and the inhibition of the secretory phenotype".Experimental Gerontology.94:89–92.doi:10.1016/j.exger.2017.01.026.PMID28167236.S2CID4960885.
  23. ^abWang R, Yu Z, Sunchu B, Perez VI (2017)."Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism".Aging Cell.16(3): 564–574.doi:10.1111/acel.12587.PMC5418203.PMID28371119.
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  27. ^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".Proceedings of the Society for Experimental Biology and Medicine.191(1): 23–9.doi:10.3181/00379727-191-42884.PMID2654945.S2CID7004908.
  28. ^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".International Journal of Radiation Oncology, Biology, Physics.20(3): 447–56.doi:10.1016/0360-3016(91)90056-A.PMID1995530.
  29. ^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".The New England Journal of Medicine.328(11): 756–61.doi:10.1056/NEJM199303183281103.PMID8437596.S2CID70718207.
  30. ^Korneev, KV; Atretkhany, KN; Drutskaya, MS; Grivennikov, SI; Kuprash, DV; Nedospasov, SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis".Cytokine.89:127–135.doi:10.1016/j.cyto.2016.01.021.PMID26854213.
  31. ^Reichert JM (2015)."Antibodies to watch in 2015".mAbs.7(1): 1–8.doi:10.4161/19420862.2015.988944.PMC4622967.PMID25484055.
  32. ^Valente Duarte de Sousa IC (Oct 2014). "Novel pharmacological approaches for the treatment of acne vulgaris".Expert Opinion on Investigational Drugs.23(10): 1389–410.doi:10.1517/13543784.2014.923401.PMID24890096.S2CID19860451.

Further reading[edit]

External links[edit]

This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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