Human interleukin 3 (IL-3) mediates its effects by binding to the human IL-3 receptor composed of an IL-3 binding α-subunit (DUK-1) and a common β-subunit also shared by the receptors for GM-CSF and IL-5. Binding of IL-3 induces the heterodimerization of the α- and the β-receptor subunit that both belong to the cytokine receptor family and together form a high-affinity receptor. Upon ligand binding the tyrosine kinase JAK2 that associates with the β-subunit is believed to be activated by transphosphorylation, and the β-subunit itself becomes phosphorylated on tyrosine residues providing docking sites for SH2- or PTB-domain containing proteins. A membrane proximal domain of the β-subunit is linked to the activation of JAK-2, induction of c-myc and pim-1, whereas a more distal region is required for the activation of the ras-pathway. Tyrosine 577 of the β-subunit mediates the binding of SHC to the β-chain at least upon stimulation with GM-CSF.
The human interleukin-3 (hIL-3) is a glycoprotein, which served as a key modulation factor of primitive hematopoietic cell proliferation and differentiation. Previous studies have shown that the combined use of IL-3 and other cytokines, including stem cell factor, thrombopoietin, FLT-3 ligand, and granulocyte colony stimulating factor can effectively stimulate the ex vivo expansion and differentiation for umbilical cord blood (UCB) CD34+ cells. The CD34 marker is found on the surface of Hematopoietic stem cells (HSCs). Previous studies have established that CD34+ cells are capable of colony formation and proliferation, features that support the designation of CD34 as a marker of stem cells.
IL-3 is an important cytokine that regulates hematopoiesis. It was previously demonstrated that IL-3 is a potent inhibitor of osteoclastogenesis and bone resorption. In the present study, the role of IL-3 on human osteoblast differentiation and bone formation was also investigated. It was found that IL-3 in a dose dependent manner increases osteoblast differentiation and matrix mineralization in human mesenchymal stem cells (MSCs). IL-3 significantly enhances the expression of osteoblast specific genes such as alkaline phosphatase, collagen type-I, osteocalcin and osteopontin; and Runx-2 and osterix transcription factors. Moreover, IL-3 induces the expression of bone morphogenetic protein-2 (BMP-2), and activates smad1/5/8. IL-3 enhances osteoblast differentiation and BMP-2 secretion through JAK/STAT pathway. Interestingly, IL-3 promotes in vivo bone regeneration ability of (mesenchymal stem cells) MSCs. Thus, It was the first time to reveal that IL-3 enhances human osteoblast differentiation and bone formation in both in vitro and in vivo conditions, and suggest its therapeutic potential for bone formation in important bone diseases.
• Barhanpurkar A P, et al. IL-3 promotes osteoblast differentiation and bone formation in human mesenchymal stem cells[J]. Biochemical and biophysical research communications, 2012, 418(4): 669-675.
• Ren Z, et al. Influence of IL-3 functional fragment on cord blood stem cell ex vivo expansion and differentiation[J]. Stem Cell Investigation, 2016, 3.