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Among the IL-12 cytokines family, which plays critical roles in shaping immune responses, IL-12 is the first identified member and therefore has attracted much attention from investigators. Indeed, it has been found that IL-12 is implicated with series of diseases such as microbial infections, autoimmune diseases and cancers.
Moreover, this cytokine also has been demonstrated as a potent stimulator of several diseases characterized by inflammatory-induced bone destruction, including but no limitation to rheumatoid arthritis and periodontitis. Thus, understanding the various functions of IL-12 will be contributed to the investigation of those diseases mentioned above.
It has been shown that lL-12 is mainly produced by antigen-presenting cells (APCs), especially dendritic cells. Its primary function is to facilitate the development of native T cells into T-helper 1 (Th1) cells. Additionally, it also has been found that IL-12 has an ability to active T cells and nature killer (NK) cells, producing some inflammatory cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Further studies have demonstrated that IFN-γ stimulation is contributed to strengthen the activity of phagocytic cells and the cytotoxic response of NK cells and CD8 T cells, making for the cell-mediated immune response. The major immunological function of IL-12 can be summarized as Figure 1.
Figure 1. Schematic drawing demonstrating the major immunological functions of IL-12. (Issaranggun B N A, et al.)
IL-12 signal transduction
Previous studies have shown that IL-12 is also involved in complex signaling in immunological cells like T cells, NK cells and DC cells (Figure 2).
Usually, IL-12 exerts its activities in immune system by binding to IL-12 receptors, which consist of two subunits of β1 and β2. The two subunits are associated with the Janus Kinase (JAK) family members Tyk2 and JAK2 respectively. Several studies have found that IL-12r-β1 is mainly contributing in ligand binding process, while IL-12R-β2 is responsible for signaling transduction process by phosphorylating the JAK2. Following, phospho-JAK2 leads to the activation of some transcription (STAT) molecules, especially STAT4. Reports found that dimerized STAT4 enters the cell nucleus, promoting or repressing the gene transcription. Thus, the STAT4 is the critical factor in IL-12 signaling pathway. Moreover, the induction of STAT4 by IL-12 may lead to promotion of IFN-γ production.
Figure 2. IL-12 signal transduction in T cells/NK cells and DC cells (Zundler S, et al.)
IL-12 and tumor suppression
Early studies have found that IL-12 involves the formation of tumor microenvironment via its various functions on different immune cells, mainly on lymphoid cells such as NK cells, T cells and ILCs. Studies have found that when treatment with IL-12, the secretion of IFN-γ is increased as a result of the stimulation of lymphoid cells, inducing most of the tumor-suppressing pathways (Figure 3). Additionally, IL-12 potentiate cytotoxic responses by NK cells and CD8 T cells (CD8+) cooperated with IFN-γ. Furthermore, IL-12 and IFN-γ potentiate cytotoxic responses by NK cells and CD8 T cells (CD8+). Moreover, studies have been demonstrated that the IFNγ also plays an important role in direct tumor vascular responses such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) up-regulation and inhibition of angiogenesis. And leukocyte recruitment to the tumor tissue is thought to be facilitated by the adhesion molecule. Besides, IFN-γ leads to the inhibition of angiogenesis by stimulating the myeloid cells, resulting in the increased secretion of Chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 and decreased production of VEGF and MMP-9.
Moreover, the stimulation of IL-12 on antigen presentation and cross-presentation by APCs has been found to promote the cytotoxic activity of CD8 T cells and cytokine response of CD4 T cells both. Additionally, the tumor suppressive effect also has been shown on GM-CSF which derived from T cells after the stimulation of IL-12.
Based on the suppression property of IL-12 on tumor, many therapeutic approaches such as recombinant IL-12 antibodies, transferred cells released IL-12 into tumors have been developed.
Figure 3. Cellular responses to IL-12 stimulation in the tumor tissue. (Tugues S, et al.)
In addition to the suppression role on tumor, IL-12 also exert important roles in periodontal disease and Central nervous system (CNS) autoimmune Disease. Thus, IL-12 is still a cytokine which possesses potent therapeutic function in clinic.