IL3

IL3 Background

Interleukin-3 (IL3) is a multipotent cytokine produced by activated T cells, monocytes/macrophages, and stroma cells that links immunity to the hemopoietic system and plays a remarkable role in leukemia as well as several immunopathologies ^[1]. Through actions on several cell types, IL3 contributes to allergic inflammation, autoimmune diseases, and oncogenesis ^[2][3]. The downstream effects of IL3 are mediated by binding to its receptor, a complex that contains an alpha subunit (IL3R or CD123) and a beta subunit (IL3Rβ or CSF2RB) ^[4]. Upon IL3 stimulation, a cascade of signaling mechanisms is elicited, including activation of the JAK2/STAT5 pathway and the PI3 kinase pathway ^[5]. Further, activation of the NF-kappa B pathway through TRAF6 recruitment to the beta subunit has been described ^[6]. These pathways not only leads to the cell-cycle progression and DNA synthesis but also suppression of apoptosis, thus facilitating cellular survival against apoptosis. IL3 is also involved in bone marrow hemopoiesis and dendritic cell maturation in anti-viral or antitumor reactivity. Since IL-3 is constitutively present in the myelomonocytic leukemia cell line WEHI-3B, it is thought that this genetic change is the key to the development of this leukemia type ^[7]. It has been shown that the combination of IL-3, GM-CSF, and stem cell factor enhances peripheral blood stem cells during high-dose chemotherapy ^[8][9]. 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 ^[10].

[1] Hercus T.R., Dhagat U., et al. Signalling by the bc family of cytokines [J]. Cytokine Growth Factor Rev. 2013, 24, 189-201.
[2] Korpelainen E.I., Gamble J.R., et al. The receptor for interleukin 3 is selectively induced in human endothelial cells by tumor necrosis factor alpha and potentiates interleukin 8 secretion and neutrophiltransmigration [J]. Proc. Natl. Acad. Sci. USA 1993, 90, 11137-11141.
[3] Broughton S.E., Dhagat U., et al. The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling [J]. Immunol. Rev. 2012, 250, 277-302.
[4] Takai S, Yamada K, et al. Mapping of the human gene encoding the mutual signal-transducing subunit (beta-chain) of granulocyte-macrophage colonystimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) receptor complexes to chromosome 22q13.1 [J]. Hum Genet 1994;93(2):198-200.
[5] Hercus TR et al. Role of the β common (βc) family of cytokines in health and disease [J]. Cold Spring Harb Perspect Biol 2018;10(6).
[6] Meads MB, Li Z-W, et al. A novel TNF receptor-associated factor 6 binding domain mediates NF-kappa B signaling by the common cytokine receptor beta subunit [J]. J Immunol 2010;185(3):1606-1615.
[7] Aiguo, Wu, Guangren, Duan. PMID Observer Design of Descriptor Linear Systems [J]. 2007 Chinese Control Conference. 2016, IEEE: 161-165.
[8] Serrano F, Varas F, et al. Accelerated and longterm hematopoietic engraftment in mice transplanted with ex-vivo expanded bone marrow [J]. Bone Marrow Transplant. 1996, 14 (6): 855-62.
[9] Peters SO, Kittler EL, et al. Ex-vivo expansion of murine marrow cells with IL-3, Il-6, Il-11 and SCF leads to impaired engraftment in irradiated host [J]. Blood. 1996, 87 (1): 30-7.
[10] Manzoor H Mangi, Adrian C Newland. Interleukin-3 in hematology and onkology: Current state of knowledge and future directions [J]. Cytokines, Cellular and Molecular Therapy. 5: 87-95.