Interleukin 1-alpha explained

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

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 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.[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 (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[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] 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,[12] 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,[13] 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.

IL1A is found on the surface of senescent cells, where it contributes to the production of senescence-associated secretory phenotype (SASP) factors.[14]

These data suggest that IL-1α is normally 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]

Translation of mRNA for IL1A is highly dependent upon mTOR activity.[18] IL1A and NF-κB mutually induce each other in a positive feedback loop.[19]

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.[20] 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.[21]

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,[22] [23] possibly as a result of hemopoietin-1 activity.[24]

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.[25] 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.[26]

An anti-IL-1α therapeutic antibody, MABp1, is being tested in clinical trials for anti-neoplastic activity in solid tumors.[27] Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.[28]

Further reading

Notes and References

  1. Nicklin MJ, Weith A, Duff GW . 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 . Jan 1994 . 8188271 . 10.1006/geno.1994.1076 .
  2. March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K . Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs . Nature . 315 . 6021 . 641–7 . August 1985 . 2989698 . 10.1038/315641a0 . 1985Natur.315..641M . 4240002 .
  3. Bankers-Fulbright JL, Kalli KR, McKean DJ . Interleukin-1 signal transduction . Life Sciences . 59 . 2 . 61–83 . 1996 . 8699924 . 10.1016/0024-3205(96)00135-X .
  4. Dinarello CA . Induction of interleukin-1 and interleukin-1 receptor antagonist . Seminars in Oncology . 24 . 3 Suppl 9 . S9–81–S9–93 . June 1997 . 9208877 .
  5. Gery I, Gershon RK, Waksman BH . Potentiation of the T-lymphocyte response to mitogens. I. The responding cell . The Journal of Experimental Medicine . 136 . 1 . 128–42 . Jul 1972 . 5033417 . 2139184 . 10.1084/jem.136.1.128 .
  6. Gery I, Waksman BH . 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 . Jul 1972 . 5033418 . 2139186 . 10.1084/jem.136.1.143 .
  7. Gery I, Handschumacher RE . Potentiation of the T lymphocyte response to mitogens. III. Properties of the mediator(s) from adherent cells . Cellular Immunology . 11 . 1–3 . 162–9 . March 1974 . 4549027 . 10.1016/0008-8749(74)90016-1 .
  8. Watanabe N, Kobayashi Y . Selective release of a processed form of interleukin 1 alpha . Cytokine . 6 . 6 . 597–601 . November 1994 . 7893968 . 10.1016/1043-4666(94)90046-9 .
  9. Hauser C, Saurat JH, Schmitt A, Jaunin F, Dayer JM . Interleukin 1 is present in normal human epidermis . Journal of Immunology . 136 . 9 . 3317–23 . May 1986 . 10.4049/jimmunol.136.9.3317 . 3007615 . 1351452 . free .
  10. Gahring LC, Buckley A, Daynes RA . Presence of epidermal-derived thymocyte activating factor/interleukin 1 in normal human stratum corneum . The Journal of Clinical Investigation . 76 . 4 . 1585–91 . Oct 1985 . 2997285 . 424137 . 10.1172/JCI112141 .
  11. Schmitt A, Hauser C, Jaunin F, Dayer JM, Saurat JH . 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 . 1986 . 3486328 .
  12. Barland CO, Zettersten E, Brown BS, Ye J, Elias PM, Ghadially R . Imiquimod-induced interleukin-1 alpha stimulation improves barrier homeostasis in aged murine epidermis . The Journal of Investigative Dermatology . 122 . 2 . 330–6 . Feb 2004 . 15009713 . 10.1046/j.0022-202X.2004.22203.x . free .
  13. Book: Durum SK, Oppenheim JJ, Feldmann M . Feldmann M, Saklatvala J . Cytokine reference: a compendium of cytokines and other mediators of host defense . registration . Academic Press . Boston . 2001 . Proinflammatory cytokines . 291–306 . 978-0-12-252673-2 .
  14. Laberge R, Sun Y, Orjalo AV, Patil CK, Campisi J . MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation . . 17 . 8 . 1049–1061 . 2015 . 10.1038/ncb3195 . 4691706 . 26147250.
  15. Yin H, Morioka H, Towle CA, Vidal M, Watanabe T, Weissbach L . Evidence that HAX-1 is an interleukin-1 alpha N-terminal binding protein . Cytokine . 15 . 3 . 122–37 . August 2001 . 11554782 . 10.1006/cyto.2001.0891 .
  16. Hu B, Wang S, Zhang Y, Feghali CA, Dingman JR, Wright TM . 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 . August 2003 . 12913118 . 187743 . 10.1073/pnas.1737765100 . 2003PNAS..10010008H . free .
  17. Book: Durum SK, Oppenheim JJ, Feldmann M . Dinarello CA . Cytokine reference: a compendium of cytokines and other mediators of host defense . Academic Press . Boston . 2001 . IL-1α . 307–318 . 978-0-12-252673-2 .
  18. Wang R, Sunchu B, Perez VI . Rapamycin and the inhibition of the secretory phenotype . . 94 . 89–92 . 2017 . 10.1016/j.exger.2017.01.026 . 28167236. 4960885 .
  19. Wang R, Yu Z, Sunchu B, Perez VI . Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism . . 16 . 3 . 564–574 . 2017 . 10.1111/acel.12587 . 5418203 . 28371119.
  20. Arend WP, Malyak M, Guthridge CJ, Gabay C . Interleukin-1 receptor antagonist: role in biology . Annual Review of Immunology . 16 . 27–55 . 1998 . 9597123 . 10.1146/annurev.immunol.16.1.27 .
  21. Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR . Interleukin-10 . Annual Review of Immunology . 11 . 165–90 . 1993 . 8386517 . 10.1146/annurev.iy.11.040193.001121 .
  22. Neta R, Douches S, Oppenheim JJ . Interleukin 1 is a radioprotector . Journal of Immunology . 136 . 7 . 2483–5 . April 1986 . 10.4049/jimmunol.136.7.2483 . 3512714 . 36193680 . free .
  23. Dorie MJ, Allison AC, Zaghloul MS, Kallman RF . 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 . May 1989 . 2654945 . 10.3181/00379727-191-42884 . 7004908 .
  24. Constine LS, Harwell S, Keng P, Lee F, Rubin P, Siemann D . 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 . March 1991 . 1995530 . 10.1016/0360-3016(91)90056-A . free .
  25. Smith JW, Longo DL, Alvord WG, Janik JE, Sharfman WH, Gause BL, Curti BD, Creekmore SP, Holmlund JT, Fenton RG . 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 . March 1993 . 8437596 . 10.1056/NEJM199303183281103 . 70718207 . free .
  26. Korneev. KV. Atretkhany. KN. Drutskaya. MS. Grivennikov. SI. Kuprash. DV. Nedospasov. SA. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis.. Cytokine. January 2017. 89. 127–135. 10.1016/j.cyto.2016.01.021. 26854213.
  27. Reichert JM . Antibodies to watch in 2015 . mAbs . 7 . 1 . 1–8 . 2015 . 25484055 . 10.4161/19420862.2015.988944 . 4622967.
  28. Valente Duarte de Sousa IC . Novel pharmacological approaches for the treatment of acne vulgaris . Expert Opinion on Investigational Drugs . 23 . 10 . 1389–410 . Oct 2014 . 24890096 . 10.1517/13543784.2014.923401 . 19860451 .

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