Wikipedia

Interleukin 3

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1.[3][4] 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.[5] The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types.[6] It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors.[7][8] It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.[9][10]

IL3
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesIL3, interleukin 3, IL-3, MCGF, MULTI-CSF
External IDsOMIM: 147740; HomoloGene: 47938; GeneCards: IL3; OMA:IL3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3562

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Ensembl

ENSG00000164399

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UniProt

P08700

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RefSeq (mRNA)

NM_000588

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RefSeq (protein)

NP_000579

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Location (UCSC)Chr 5: 132.06 – 132.06 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Function

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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.[10] 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.[9][10]

IL-3 is mainly produced by activated T cells with the goal of initiating proliferation of various other immune cell types.[8] However, IL-3 has also been shown to be produced in IgG+ B cells and may be involved in earlier antibody isotype switching.[9]  IL-3 is capable of stimulating differentiation of immature myelomonocytic cells causing changes to the macrophage and granulocyte populations.[8] 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.[10]

IL-3 also induces various effector functions in both immature and mature cells that more precisely modulate the body’s defense against microbial pathogens.[8][10] IL-3 is also involved in the reconstruction of platelets via the development of megakaryocytes.[10]

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

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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.[11] 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).[12] This β subunit sharing explains the biological functional similarities of different hematopoietic growth factors.[13]

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.[10]

IL-3/Receptor complex induces JAK2/STAT5 cell signalization pathway.[8] It can stimulate transcription factor c‑myc (activation of gene expression) and Ras pathway (suppression of apoptosis).[5]

Discovery

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In the early 1960s Ginsberg and Sachs discovered that IL-3 is a potent mast cell growth factor produced from activated T cells.[11] 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).[14][15]

Disease

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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.[6] 

Immunological therapy

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Human IL-3 was first cloned in 1986 and since then clinical trials are ongoing.[16] 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.[13]

It has been shown that combination of IL-3, GM-CSF and stem cell factor enhances peripheral blood stem cells during high-dose chemotherapy.[17][18]

Other studies showed that IL-3 could be a future perspective therapeutic agent in lymphohematopoietic disorders and solid cancers.[19]

Interactions

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Interleukin 3 has been shown to interact with IL3RA.[20][21]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000164399 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Entrez Gene: IL3 interleukin 3 (colony-stimulating factor, multiple)".
  4. ^ Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG (October 1986). "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. doi:10.1016/0092-8674(86)90360-0. PMID 3489530. S2CID 37207637.
  5. ^ a b "IL3 (interleukin-3)". atlasgeneticsoncology.org. Archived from the original on 2022-02-05. Retrieved 2019-06-19.
  6. ^ a b Aiguo W, Guangren D (July 2006). "PMID Observer Design of Descriptor Linear Systems". 2007 Chinese Control Conference. IEEE. pp. 161–165. doi:10.1109/chicc.2006.4347343. ISBN 978-7-81124-055-9. S2CID 72187.
  7. ^ 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. doi:10.1002/stem.5530110814. ISSN 1066-5099. PMID 8401260. S2CID 27772987.
  8. ^ a b c d e Guthridge MA, Stomski FC, Thomas D, Woodcock JM, Bagley CJ, Berndt MC, Lopez AF (September 1998). "Mechanism of Activation of the GM-CSF, IL-3, and IL-5 Family of Receptors". Stem Cells. 16 (5): 301–313. doi:10.1002/stem.160301. ISSN 1066-5099. PMID 9766809.
  9. ^ a b c Wang AA, Gommerman JL, Rojas OL (January 2021). "Plasma Cells: From Cytokine Production to Regulation in Experimental Autoimmune Encephalomyelitis". Journal of Molecular Biology. 433 (1): 166655. doi:10.1016/j.jmb.2020.09.014. ISSN 0022-2836. PMID 32976908.
  10. ^ a b c d e f g Dougan M, Dranoff G, Dougan SK (April 2019). "GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation". Immunity. 50 (4): 796–811. doi:10.1016/j.immuni.2019.03.022. ISSN 1074-7613. PMID 30995500.
  11. ^ a b Delves, Peter J., Roitt, Ivan Maurice, eds. (1998). Encyclopedia of immunology (2nd ed.). San Diego: Academic Press. ISBN 0-12-226765-6. OCLC 36017792.
  12. ^ 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. doi:10.1007/bf00210610. ISSN 0340-6717. PMID 8112746. S2CID 34492340.
  13. ^ a b Manzoor H Mangi AC (1999). "Interleukin-3 in hematology and onkology: Current state of knowledge and future directions". Cytokines, Cellular and Molecular Therapy. 5 (2): 87–95. PMID 10515681.
  14. ^ Ihle JN, Pepersack L, Rebar L (June 1981). "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. doi:10.4049/jimmunol.126.6.2184. PMID 6971890. S2CID 20592584.
  15. ^ Ihle JN, Weinstein Y, Keller J, Henderson L, Palaszynski E (1985). "Interleukin 3". Immunochemical Techniques Part H. Methods in Enzymology. Vol. 116. pp. 540–52. doi:10.1016/S0076-6879(85)16042-8. ISBN 978-0-12-182016-9. PMID 3003517.
  16. ^ Metcalf D, Begley CG, Johnson GR, et al. (1986). "Effects of purified bacterially synthesised murine multi CSF (IL3) on hematopoiesis in normal adult mice". Blood. 68 (1): 46–57. doi:10.1182/blood.V68.1.46.46. PMID 3087441.
  17. ^ Serrano F, Varas F, Bernard A, Bueren JA (1994). "Accelerated and longterm hematopoietic engraftment in mice transplanted with ex-vivo expanded bone marrow". Bone Marrow Transplant. 14 (6): 855–62. PMID 7711665.
  18. ^ Peters SO, Kittler EL, Ramshaw HS, Quesenberry PJ (1996). "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. doi:10.1182/blood.V87.1.30.30. PMID 8547656.
  19. ^ Hirst W, 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. doi:10.1038/sj.gt.3300437. ISSN 0969-7128. PMID 9282170.
  20. ^ Stomski FC, Sun Q, Bagley CJ, Woodcock J, Goodall G, Andrews RK, Berndt MC, Lopez AF (June 1996). "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. doi:10.1128/MCB.16.6.3035. PMC 231298. PMID 8649415.
  21. ^ Woodcock JM, Zacharakis B, Plaetinck G, Bagley CJ, Qiyu S, Hercus TR, Tavernier J, Lopez AF (November 1994). "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. doi:10.1002/j.1460-2075.1994.tb06848.x. PMC 395466. PMID 7957082.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: P08700 (Interleukin-3) at the PDBe-KB.
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