Interleukin 3

Last updated
IL3
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases IL3 , interleukin 3, IL-3, MCGF, MULTI-CSF
External IDs OMIM: 147740 HomoloGene: 47938 GeneCards: IL3
Orthologs
SpeciesHumanMouse
Entrez

3562

n/a

Ensembl

ENSG00000164399

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UniProt

P08700

n/a

RefSeq (mRNA)

NM_000588

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RefSeq (protein)

NP_000579

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

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]

Contents

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 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

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

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Haematopoiesis</span> Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.

<span class="mw-page-title-main">Granulocyte colony-stimulating factor</span> Mammalian protein found in humans

Granulocyte colony-stimulating factor, also known as colony-stimulating factor 3, is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor</span> Mammalian protein found in Homo sapiens

Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.

<span class="mw-page-title-main">Interleukin 1-alpha</span> Protein-coding gene in the species Homo sapiens

Interleukin-1 alpha also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the IL1A gene. 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.

<span class="mw-page-title-main">Macrophage colony-stimulating factor</span> Mammalian protein found in humans

The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types. Eukaryotic cells also produce M-CSF in order to combat intercellular viral infection. It is one of the three experimentally described colony-stimulating factors. M-CSF binds to the colony stimulating factor 1 receptor. It may also be involved in development of the placenta.

<span class="mw-page-title-main">Granulopoiesis</span> Part of haematopoiesis, that leads to the production of granulocytes

Granulopoiesis is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. Granulopoiesis takes place in the bone marrow. It leads to the production of three types of mature granulocytes: neutrophils, eosinophils and basophils.

Interleukin 27 (IL-27) is a member of the IL-12 cytokine family. It is a heterodimeric cytokine that is encoded by two distinct genes, Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28. IL-27 is expressed by antigen presenting cells and interacts with a specific cell-surface receptor complex known as IL-27 receptor (IL-27R). This receptor consists of two proteins, IL-27Rɑ and gp130. IL-27 induces differentiation of the diverse populations of T cells in the immune system and also upregulates IL-10.

Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name hemopoietin receptors, and share a common amino acid motif (WSXWS) in the extracellular portion adjacent to the cell membrane. Members of the type I cytokine receptor family comprise different chains, some of which are involved in ligand/cytokine interaction and others that are involved in signal transduction.

<span class="mw-page-title-main">Granulocyte colony-stimulating factor receptor</span> Protein-coding gene in the species Homo sapiens

The granulocyte colony-stimulating factor receptor (G-CSF-R) also known as CD114 is a protein that in humans is encoded by the CSF3R gene. G-CSF-R is a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF). The G-CSF receptors belong to a family of cytokine receptors known as the hematopoietin receptor family. The granulocyte colony-stimulating factor receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor receptor</span> Protein-coding gene in humans

The granulocyte-macrophage colony-stimulating factor receptor, also known as CD116, is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. In contrast to M-CSF and G-CSF which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on neutrophils, eosinophils and monocytes/macrophages, it is also on CD34+ progenitor cells (myeloblasts) and precursors for erythroid and megakaryocytic lineages, but only in the beginning of their development.

<span class="mw-page-title-main">FMS-like tyrosine kinase 3 ligand</span> Protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 3 ligand (FLT3LG) is a protein which in humans is encoded by the FLT3LG gene.

<span class="mw-page-title-main">Colony stimulating factor 1 receptor</span> Protein found in humans

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

<span class="mw-page-title-main">Interleukin 5 receptor alpha subunit</span> Protein-coding gene in the species Homo sapiens

Interleukin 5 receptor, alpha (IL5RA) also known as CD125 is a subunit of the Interleukin-5 receptor. IL5RA also denotes its human gene.

<span class="mw-page-title-main">IL3RA</span> Human gene

Interleukin 3 receptor, alpha (IL3RA), also known as CD123, is a human gene.

The interleukin-5 receptor is a type I cytokine receptor. It is a heterodimer of the interleukin 5 receptor alpha subunit and CSF2RB.

<span class="mw-page-title-main">CFU-GEMM</span>

CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyte, erythrocyte, monocyte, megakaryocyte.

Lenzilumab is a humanized monoclonal antibody that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF).

References

  1. 1 2 3 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. 1 2 "IL3 (interleukin-3)". atlasgeneticsoncology.org. Archived from the original on 2022-02-05. Retrieved 2019-06-19.
  6. 1 2 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. 1 2 3 4 5 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. 1 2 3 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. 1 2 3 4 5 6 7 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. 1 2 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. 1 2 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.

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