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: the protein contains 152 amino acids and its molecular weight is 17 kDa. 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
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

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 linages 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

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

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

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

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

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

See also

References
  1. 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. "IL3 (interleukin-3)". atlasgeneticsoncology.org. Archived from the original on 2022-02-05. Retrieved 2019-06-19.
  6. Aiguo, Wu; Guangren, Duan (July 2006). "PMID Observer Design of Descriptor Linear Systems". 2007 Chinese Control Conference. IEEE. pp. 161–165. doi:10.1109/chicc.2006.4347343. ISBN 9787811240559. 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. 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. doi:10.1002/stem.160301. ISSN 1066-5099. PMID 9766809.
  9. 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. doi:10.1016/j.jmb.2020.09.014. ISSN 0022-2836. PMID 32976908.
  10. 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. doi:10.1016/j.immuni.2019.03.022. ISSN 1074-7613. PMID 30995500.
  11. Delves, Peter J.; Roitt, Ivan Maurice, eds. (1998). Encyclopedia of immunology (2nd ed.). San Diego: Academic Press. ISBN 0122267656. 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. Manzoor H Mangi, Adrian C Newland (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). "[40] Interleukin 3". Immunochemical Techniques Part H. pp. 540–52. doi:10.1016/S0076-6879(85)16042-8. ISBN 978-0-12-182016-9. PMID 3003517. {{cite book}}: |journal= ignored (help)
  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, 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. 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
  • Overview of all the structural information available in the PDB for UniProt: P08700 (Interleukin-3) at the PDBe-KB.
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