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Interleukins 15 (IL-15) plays pleiotropic biological functions including dictating T cell response, regulating tissue repair and B cell homing, modulating inflammation, and activating NK cells. Thus, it is considered as a potential therapeutic target in diseases such as obesity, type 2 diabetes (T2D), cancer and T cell immunity responses.
It is generally accepted that IL-15 effects its biological function via two signaling pathways, one called classical signaling and another called tran-signaling (Figure 1).
Figure 1. IL-15 signaling pathway. (Guo Y, et al. 2017)
It has been shown that IL-15-mediated its signals via binding to IL-15 receptor, which consists of β and γ subunits. Upon binding of IL-15 to IL-15 receptor in responding cells, the Janus kinase 1 (Jak1) and Jak3 is phosphorylated and activated respectively. Activated Jak1 and Jak3 further leads to phosphorylation of signal transducer and activator of transcription proteins 3 and 5 (STAT3 and STAT5), which activates downstream signaling molecules such as PI3K/AKT and Ras/Raf MAP kinase that might mediate the gene transcriptional regulation of IL-15. Although IL-15 is presented by high affinity receptor α, it can bind to the intermediate-affinity β and γ receptor complex without receptor α in some case, activating other tyrosine kinases including lymphocyte-specific protein tyrosine kinase (Lck), Fyn, Lyn, Spleen tyrosine kinase (Syk) and cross talk with the PI3K and mitogen-activated protein kinase (MAPK) pathways.
Figure 2. Pleiotropic biological roles of IL-15 on cells. (Patidar M, et al. 2016)
Studies have found that IL-15 exerts its functions on various cells including immunological cells and non-immune cells. It has been shown that IL-15 is implicated with activation of T cells that is critical for adaptive immune response. IL-15 has been demonstrated to effect on the survival of naive and memory CD8+ T cell. Several studies have reported that IL-15 maintains memory T cell response by inhibiting the activation induced cell death (AICD) of effector T cells which is induced by IL-2. Moreover, it has been shown that IL-15 alters the expression of CCR7 and CD62L to regulate T-cell migration resisting infection.
Additionally, IL-15 also acts the inhibition of apoptosis on B cells via promoting survival signal pathway IL-15–SyK–PCL1 and inhibiting anti-IgM-induced apoptosis. Moreover, studies have shown that IL-15 signals, such as IL-15–STAT5 and IL-15–SHC–Ras–Raf–ERK, are implicated with B cell proliferation, class-switching as well as antibody secretion. For instance, IL-15 enhances the proliferation of anti-HIV B-cells and Ig production in case of HIV. Based on these roles, IL-15 is considered as a useful target in humoral response. IL-15 also has been found to regulate B cell homing via inhibiting cytoskeletal rearrangement and migration.
In addition, it has been found that IL-15 is involved in the survival, maturation, proliferation, and anti-viral activity of NK cells. Upon binding of IL-15 to IL-15R on NK cells, three pathways including the Ras–Raf–MAP kinase, STAT5, and mammalian target of rapamycin (mTOR) pathways are evoked depending on the status of NK cells and infection conditions. Studies also found that activation of IL-15 on dendritic cells stimulates the cytotoxic as well as antitumor activity of NK cells.
Moreover, other immunological cells such as mast cell, dendritic cells and neutrophils are also influenced by IL-15. It has been shown that IL-15 activates neutrophils by stimulating RNA synthesis, cytoskeletal rearrangement, and morphological changes, and regulates phagocytosis of neutrophils by controlling Syk expression. Previous studies have found that IL-15 binds to IL-15RX, a unique receptor of IL-15 on mast cell, inducing mast cell growth by activation of JAK2/STAT5 pathways and differentiation by TYK2/STAT6/IL-4 pathway.