Interleukin 3 Explained

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1.^{[1] [2]} Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: after removal of the signal peptide sequence, the mature protein contains 133 amino acids in its polypeptide chain. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells.^[3] The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types.^[4] It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors.^{[5] [6]} It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.^{[7] [8]}

Function

Interleukin 3 is an interleukin, a type of biological signal (cytokine) that can improve the body's natural response to disease as part of the immune system. In conjunction with other β common chain cytokines GM-CSF and IL-5, IL-3 works to regulate the inflammatory response in order to clear pathogens by changing the abundance of various cell populations via binding at the interleukin-3 receptor.

IL-3 is mainly produced by activated T cells with the goal of initiating proliferation of various other immune cell types. However, IL-3 has also been shown to be produced in IgG+ B cells and may be involved in earlier antibody isotype switching.  IL-3 is capable of stimulating differentiation of immature myelomonocytic cells causing changes to the macrophage and granulocyte populations. IL-3 signaling is able to give rise to widest array of cell lineages which is why it has been independently named “multi-CSF” in some older literature.

IL-3 also induces various effector functions in both immature and mature cells that more precisely modulate the body’s defense against microbial pathogens. IL-3 is also involved in the reconstruction of platelets via the development of megakaryocytes.

Interleukin 3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells or, with the addition of IL-7, into lymphoid progenitor cells. In addition, IL-3 stimulates proliferation of all cells in the myeloid lineage (granulocytes, monocytes, and dendritic cells), in conjunction with other cytokines, e.g., Erythropoietin (EPO), Granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-6.

IL-3 is secreted by basophils and activated T cells to support growth and differentiation of T cells from the bone marrow in an immune response. Activated T cells can either induce their own proliferation and differentiation (autocrine signaling), or that of other T cells (paracrine signaling) – both involve IL-2 binding to the IL-2 receptor on T cells (upregulated upon cell activation, under the induction of macrophage-secreted IL-1). The human IL-3 gene encodes a protein 152 amino acids long, and the naturally occurring IL-3 is glycosylated. The human IL-3 gene is located on chromosome 5, only 9 kilobases from the GM-CSF gene, and its function is quite similar to GM-CSF.

Receptor

IL-3 is a T cell-derived, pluripotent and hematopoietic factor required for survival and proliferation of hematopoietic progenitor cells. The signal transmission is ensured by high affinity between cell surface interleukin-3 receptor and IL-3.^[9] This high affinity receptor contains α and β subunits. IL-3 shares the β subunit with IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF).^[10] This β subunit sharing explains the biological functional similarities of different hematopoietic growth factors.^[11]

IL-3 receptors can be found on a variety of cell types including many immature myelomonocytic cells in the hemopoietic system such as hemopoietic progenitor cells, as well as certain myeloid progenitors, basophils, and eosinophils.

IL-3/Receptor complex induces JAK2/STAT5 cell signalization pathway. It can stimulate transcription factor c‑myc (activation of gene expression) and Ras pathway (suppression of apoptosis).

Discovery

In the early 1960s Ginsberg and Sachs discovered that IL-3 is a potent mast cell growth factor produced from activated T cells. Interleukin 3 was originally discovered in mice and later isolated from humans. The cytokine was originally discovered via the observation that it induced the synthesis of 20alpha-hydroxysteroid dehydrogenase in hematopoietic cells and termed it interleukin-3 (IL-3).^{[12] [13]}

Disease

IL-3 is produced by T cells only after stimulation with antigens or other specific impulses.

However, it was observed that IL-3 is present in the myelomonocytic leukaemia cell line WEHI-3B. It is thought that this genetic change is the key in development of this leukemia type.^[4]  

Immunological therapy

Human IL-3 was first cloned in 1986 and since then clinical trials are ongoing.^[14] Post-chemotherapy, IL-3 application reduces chemotherapy delays and promotes regeneration of granulocytes and platelets. However, only IL-3 treatment in bone marrow failure disorders such as myelodysplastic syndrome (MDS) and aplastic anemia (AA) was disappointing.

It has been shown that combination of IL-3, GM-CSF and stem cell factor enhances peripheral blood stem cells during high-dose chemotherapy.^{[15] [16]}

Other studies showed that IL-3 could be a future perspective therapeutic agent in lymphohematopoietic disorders and solid cancers.^[17]

Interactions

Interleukin 3 has been shown to interact with IL3RA.^{[18] [19]}

See also

• Interleukin

Further reading

• Wagemaker G, Burger H, van Gils FC, van Leen RW, Wielenga JJ . Interleukin-3 . Biotherapy . 2 . 4 . 337–45 . 1990 . 2268499 . 10.1007/BF02170083 . 195122011 .
• Martinez-Moczygemba M, Huston DP . Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF . J. Allergy Clin. Immunol. . 112 . 4 . 653–65; quiz 666 . 2003 . 14564341 . 10.1016/j.jaci.2003.08.015 .
• Mroczko B, Szmitkowski M . Hematopoietic cytokines as tumor markers . Clin. Chem. Lab. Med. . 42 . 12 . 1347–54 . 2004 . 15576295 . 10.1515/CCLM.2004.253 . 11414705 .
• Kitamura T, Sato N, Arai K, Miyajima A . Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors . Cell . 66 . 6 . 1165–74 . 1991 . 1833064 . 10.1016/0092-8674(91)90039-2 . 42948973 .
• Urdal DL, Price V, Sassenfeld HM, Cosman D, Gillis S, Park LS . Molecular characterization of colony-stimulating factors and their receptors: human interleukin-3 . Ann. N. Y. Acad. Sci. . 554 . 1. 167–76 . 1989 . 2544122 . 10.1111/j.1749-6632.1989.tb22418.x . 1989NYASA.554..167U . 35647863 .
• Otsuka T, Miyajima A, Brown N, Otsu K, Abrams J, Saeland S, Caux C, de Waal Malefijt R, de Vries J, Meyerson P . Isolation and characterization of an expressible cDNA encoding human IL-3. Induction of IL-3 mRNA in human T cell clones . J. Immunol. . 140 . 7 . 2288–95 . 1988 . 10.4049/jimmunol.140.7.2288 . 3127463 . 10373990 . free .
• Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG . Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3 . Cell . 47 . 1 . 3–10 . 1986 . 3489530 . 10.1016/0092-8674(86)90360-0 . 37207637 .
• Le Beau MM, Epstein ND, O'Brien SJ, Nienhuis AW, Yang YC, Clark SC, Rowley JD . The interleukin 3 gene is located on human chromosome 5 and is deleted in myeloid leukemias with a deletion of 5q . Proc. Natl. Acad. Sci. U.S.A. . 84 . 16 . 5913–7 . 1987 . 3497400 . 298973 . 10.1073/pnas.84.16.5913 . 1987PNAS...84.5913L . free .
• Dorssers L, Burger H, Bot F, Delwel R, Geurts van Kessel AH, Löwenberg B, Wagemaker G . Characterization of a human multilineage-colony-stimulating factor cDNA clone identified by a conserved noncoding sequence in mouse interleukin-3 . Gene . 55 . 1 . 115–24 . 1987 . 3497843 . 10.1016/0378-1119(87)90254-X .
• Chirmule N, Goonewardena H, Pahwa S, Pasieka R, Kalyanaraman VS, Pahwa S . HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells . J. Biol. Chem. . 270 . 33 . 19364–9 . 1995 . 7642615 . 10.1074/jbc.270.33.19364 . free .
• Than S, Oyaizu N, Pahwa RN, Kalyanaraman VS, Pahwa S . Effect of human immunodeficiency virus type-1 envelope glycoprotein gp160 on cytokine production from cord-blood T cells . Blood . 84 . 1 . 184–8 . 1994 . 8018916 . 10.1182/blood.V84.1.184.184. free .
• Le Beau MM, Espinosa R, Neuman WL, Stock W, Roulston D, Larson RA, Keinanen M, Westbrook CA . Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases . Proc. Natl. Acad. Sci. U.S.A. . 90 . 12 . 5484–8 . 1993 . 8516290 . 46745 . 10.1073/pnas.90.12.5484 . 1993PNAS...90.5484B . free .
• Stomski FC, Sun Q, Bagley CJ, Woodcock J, Goodall G, Andrews RK, Berndt MC, Lopez AF . Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding . Mol. Cell. Biol. . 16 . 6 . 3035–46 . 1996 . 8649415 . 231298 . 10.1128/MCB.16.6.3035.
• Feng Y, Klein BK, McWherter CA . Three-dimensional solution structure and backbone dynamics of a variant of human interleukin-3 . J. Mol. Biol. . 259 . 3 . 524–41 . 1996 . 8676386 . 10.1006/jmbi.1996.0337 . 10.1.1.521.3736 .
• Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD . P110delta, a novel phosphoinositide 3-kinase in leukocytes . Proc. Natl. Acad. Sci. U.S.A. . 94 . 9 . 4330–5 . 1997 . 9113989 . 20722 . 10.1073/pnas.94.9.4330 . 1997PNAS...94.4330V . free .
• Klein BK, Feng Y, McWherter CA, Hood WF, Paik K, McKearn JP . The receptor binding site of human interleukin-3 defined by mutagenesis and molecular modeling . J. Biol. Chem. . 272 . 36 . 22630–41 . 1997 . 9278420 . 10.1074/jbc.272.36.22630 . free .
• Sanchez X, Suetomi K, Cousins-Hodges B, Horton JK, Navarro J . CXC chemokines suppress proliferation of myeloid progenitor cells by activation of the CXC chemokine receptor 2 . J. Immunol. . 160 . 2 . 906–10 . 1998 . 10.4049/jimmunol.160.2.906 . 9551928 . 25068171 . free .
• Tabira T, Chui DH, Fan JP, Shirabe T, Konishi Y . Interleukin-3 and interleukin-3 receptors in the brain . Ann. N. Y. Acad. Sci. . 840 . 1. 107–16 . 1998 . 9629242 . 10.1111/j.1749-6632.1998.tb09554.x . 1998NYASA.840..107T . 30047980 .
• Nilsen EM, Johansen FE, Jahnsen FL, Lundin KE, Scholz T, Brandtzaeg P, Haraldsen G . Cytokine profiles of cultured microvascular endothelial cells from the human intestine . Gut . 42 . 5 . 635–42 . 1998 . 9659156 . 1727090 . 10.1136/gut.42.5.635 .

Notes and References

1. Web site: Entrez Gene: IL3 interleukin 3 (colony-stimulating factor, multiple).
2. Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG . Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3 . Cell . 47 . 1 . 3–10 . October 1986 . 3489530 . 10.1016/0092-8674(86)90360-0 . 37207637 .
3. Web site: IL3 (interleukin-3). atlasgeneticsoncology.org. 2019-06-19. 2022-02-05. https://web.archive.org/web/20220205225835/http://atlasgeneticsoncology.org/Genes/GC_IL3.html. dead.
4. Book: Aiguo. Wu. Guangren. Duan. 2007 Chinese Control Conference . PMID Observer Design of Descriptor Linear Systems . July 2006. IEEE. 161–165. 10.1109/chicc.2006.4347343. 978-7-81124-055-9. 72187.
5. Aglietta. M.. Pasquino. P.. Sanavio. F.. Stacchini. A.. Severino. A.. Fubini. L.. Morelli. S.. Volta. C.. Monteverde. A.. 1996-01-01. Granulocyte-Macrophage colony stimulating factor and interleukin 3: Target cells and kinetics of response in vivo. Stem Cells. 11. S2. 83–87. 10.1002/stem.5530110814. 1066-5099. 8401260. 27772987.
6. Guthridge. Mark A.. Stomski. Frank C.. Thomas. Daniel. Woodcock. Joanna M.. Bagley. Christopher J.. Berndt. Michael C.. Lopez. Angel F.. September 1998. Mechanism of Activation of the GM-CSF, IL-3, and IL-5 Family of Receptors. Stem Cells. 16. 5. 301–313. 10.1002/stem.160301. 9766809. 1066-5099. free.
7. Wang. Angela A.. Gommerman. Jennifer L.. Rojas. Olga L.. January 2021. Plasma Cells: From Cytokine Production to Regulation in Experimental Autoimmune Encephalomyelitis. Journal of Molecular Biology. 433. 1. 166655. 10.1016/j.jmb.2020.09.014. 32976908. 0022-2836. free.
8. Dougan. Michael. Dranoff. Glenn. Dougan. Stephanie K.. April 2019. GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation. Immunity. 50. 4. 796–811. 10.1016/j.immuni.2019.03.022. 30995500. 1074-7613. free.
9. Book: Encyclopedia of immunology. 1998. Academic Press. Delves, Peter J.. Roitt, Ivan Maurice. 0-12-226765-6. 2nd. San Diego. 36017792. registration.
10. Takai. S.. Yamada. K.. Hirayama. N.. Miyajima. A.. Taniyama. T.. February 1994 . Mapping of the human gene encoding the mutual signal-transducing subunit (?-chain) of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) receptor complexes to chromosome 22q13.1. Human Genetics. 93. 2. 198–200. 10.1007/bf00210610. 8112746. 34492340. 0340-6717.
11. Manzoor H Mangi. Adrian C Newland. Interleukin-3 in hematology and onkology: Current state of knowledge and future directions. Cytokines, Cellular and Molecular Therapy. 1999 . 5. 2 . 87–95. 10515681 .
12. Ihle JN, Pepersack L, Rebar L . Regulation of T cell differentiation: in vitro induction of 20 alpha-hydroxysteroid dehydrogenase in splenic lymphocytes from athymic mice by a unique lymphokine . J. Immunol. . 126 . 6 . 2184–9 . June 1981 . 10.4049/jimmunol.126.6.2184 . 6971890 . 20592584 . free .
13. Book: Ihle JN, Weinstein Y, Keller J, Henderson L, Palaszynski E . Immunochemical Techniques Part H . Interleukin 3 . 116 . 540–52 . 1985 . 3003517 . 10.1016/S0076-6879(85)16042-8 . 978-0-12-182016-9 . Methods in Enzymology .
14. Metcalf D, Begley CG, Johnson GR, etal. Effects of purified bacterially synthesised murine multi CSF (IL3) on hematopoiesis in normal adult mice. Blood. 68. 1. 46–57. 3087441. 1986. 10.1182/blood.V68.1.46.46. free.
15. Serrano F, Varas F, Bernard A, Bueren JA. Accelerated and longterm hematopoietic engraftment in mice transplanted with ex-vivo expanded bone marrow. Bone Marrow Transplant. 14. 6. 855–62. 7711665. 1994.
16. Peters SO, Kittler EL, Ramshaw HS, Quesenberry PJ. Ex-vivo expansion of murine marrow cells with IL-3, Il-6, Il-11 and SCF leads to impaired engraftment in irradiated host. Blood. 87. 1. 30–7. 8547656. 1996. 10.1182/blood.V87.1.30.30. free.
17. Hirst. WJR. Buggins. A. Darling. D. Gäken. J. Farzaneh. F. Mufti. GJ. July 1997 . Enhanced immune costimulatory activity of primary acute myeloid leukaemia blasts after retrovirus-mediated gene transfer of B7.1. Gene Therapy. 4. 7. 691–699. 10.1038/sj.gt.3300437. 9282170. 0969-7128. free.
18. Stomski FC, Sun Q, Bagley CJ, Woodcock J, Goodall G, Andrews RK, Berndt MC, Lopez AF . Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding . Mol. Cell. Biol. . 16 . 6 . 3035–46 . June 1996 . 8649415 . 231298 . 10.1128/MCB.16.6.3035.
19. Woodcock JM, Zacharakis B, Plaetinck G, Bagley CJ, Qiyu S, Hercus TR, Tavernier J, Lopez AF . Three residues in the common beta chain of the human GM-CSF, IL-3 and IL-5 receptors are essential for GM-CSF and IL-5 but not IL-3 high affinity binding and interact with Glu21 of GM-CSF . EMBO J. . 13 . 21 . 5176–85 . November 1994 . 7957082 . 395466 . 10.1002/j.1460-2075.1994.tb06848.x.