Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3gene 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]
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]
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/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]
^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. ISSN1066-5099. PMID8401260. S2CID27772987.
^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. ISSN0340-6717. PMID8112746. S2CID34492340.
^ abManzoor 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. PMID10515681.
^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. PMID7711665.
Kitamura T, Sato N, Arai K, Miyajima A (1991). "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. doi:10.1016/0092-8674(91)90039-2. PMID1833064. S2CID42948973.
Dorssers L, Burger H, Bot F, Delwel R, Geurts van Kessel AH, Löwenberg B, Wagemaker G (1987). "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. doi:10.1016/0378-1119(87)90254-X. PMID3497843.
