Interferon type II
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A sole member makes up the type II interferons (IFNs) that is called IFN-γ (gamma). Mature IFN-γ is an anti-parallel homodimer, which binds to the IFN-γ receptor (IFNGR) complex to elicit a signal within its target cell. IFNGR is made up of two subunits each of molecules designated IFNGR1 and IFNGR2.
Interferon- γ is a cytokine that have an important role in adaptative and innate immunity. Thus, it helps fight against some bacteria and inhibit viral replication. Moreover, this cytokine stimulates and modulate immune system. It belongs to Type II interferon and it is the only one in this class. It is serologically different from interferon type 1 as well as binds to different receptors and is encoded by a separate chromosomal locus.
Interferon-γ is secreted by a huge number of cells as well as is involved in the regulation of others. As an immune response, this homodimer is released by natural killer (NK) and natural killer T (NKT). When the antigen-specific immunity complex develops, it is produced by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cell. Furthermore, non-cytotoxic innate lymphoid cells (ILC) as well as mucosal epithelial cells, macrophages and B cells secrete IFN-γ.
The presence of IFN-γ in T helper cells makes that undifferentiated CD4+ cells (Th0 cells) to differentiated into Th1 cells. Therefore, there is a positive feedback loop which suppress Th2 cell differentiation. The defense against an infection is led by NK cells when they secrete the interferon, whereas the adaptative immune response is directed by mainly T lymphocytes with interferon-gamma.
APCs release a sort of cytokines that control the production of IFN-gamma. This cytokines are IL-12 and IL-18 which serve to connect the infection with IFN-gamma production in the innate immunity response. Once macrophages recognize pathogens, it causes the secretion of IL-12 and chemokines. These chemokines attract NK cells to the inflammation, and IL-12 bring about IFN-gamma synthesis in these cells. Apart from macrophages and NK cells, the production of the interferon-gamma by T cells is controlled by these two interleukin.
Glucocorticoids, transforming growth factor-B, IL-4 and IL-10 are negative regultors for production of IFN-gamma.
Properties of IFN-γ
Once is IFN-γ is exposed, the main functions will be the activation of macrophages and the induction of Class II major histocompatibility complex (MHC) molecule expression. Nevertheless, IFN-γ is implicated in many function within immune system as immunoregulatory, antiviral and anti-tumor properties. What's more, it carries out the transcription of 30 genes which are related with cellular and physiological responses. Principal effects of this citokyne are:
- Promotion of Natural Killer cell activity
- Increase of antigen presentation and lysosome activity of macrophages
- Activation of inducible nitric oxide synthase (iNOS)
- Induction of the production of IgG2a and IgG3 from activated plasma B cells
- Cause normal cells to increase the expression of class I MHC molecules as well as II on antigen-presenting cells
- Promotion of adhesion and binding of the expression intrinsic defense factors
Sources and functions
IFN-γ is involved in the regulation of the immune and inflammatory responses; in humans, there is only one type of interferon-gamma. It is produced in activated T-cells and natural killer cells. IFN-γ has some anti-viral and anti-tumor effects, but these are generally weak. However, this cytokine potentiates the effects of the type I IFNs. IFN-γ released by Th1 cells recruits leukocytes to a site of infection, resulting in increased inflammation. It also stimulates macrophages to kill bacteria that have been engulfed. IFN-γ released by Th1 cells is also important in regulating the Th2 response. As IFN-γ is vitally implicated in the regulation of immune response, its production can lead to autoimmune disorders.
Homologs of interferon-gamma are found in birds, frogs, and teleost fish. Thus it is likely that all bony fish/tetrapods encode IFN-γ. The gene structure of IFN-γ is identical to that of its structurally related cytokines, except that the intron between the third and fourth exons does not exist.
Notably, many teleost fish encode two distinct IFN-γ species (called IFN-γ1 and IFN-γ2) that appear to bind genetically and physically distinct IFN-γR1 chains. In all investigated tetrapods, there is a single IFN-γ gene that binds a unique IFN-γR1 chain and (in amniotes) a unique IFN-γR2 chain. Frogs appear to encode two distinct IFN-γR2 genes whose intracellular domains differ significantly.
IFN-gamma receptor (IFNGR) is formed by two ligand-binding IFNGR1 chains linked with two signal-transducing IFNGR2 chains and associated signaling machinery. Both chains belong to the class II cytokine receptor family. The IFNGR2 chain is generally the limiting factor in IFN-gamma responsiveness, whereas the IFNGR1 chain is usually in excess.
IFNGR2 is an intracellular region which have a noncontiguous binding motif for recruitment of Jak2 kinase for signaling. This chain is not tyrosine phosphorylated during signal transduction.
The expression of IFNGR2 chain depends on the state of cellular differentiation or activation. For instance, there are some CD4 Th1 cells that have low levels of IFNGR2 expression in their surface. This leads to a low expression or IFN-gamma receptor and consequently, to a functional blockade of IFN-gamma signaling.
The intracellular domain contains binding motifs for Jak1 and the latent cytosolic factor, signal transducer and activator of transcription Stat1. Jak1 as well as Stat1 are required for receptor phosphorylation, signaling transduction and induction of biological response.
Relation between colorectal cancer and IFN-gamma
It is known, from different studies, that a scarcity of this homodimer or its receptor promotes colorectal cancer development. It was studied that synergistic activation mediator-derived (SAM) can cause a specified expression of interferon-gamma and, thus activates innate immunity and inhibits tumorgenesis.
Several studies show that anti-proliferative activity of INF-gamma direct to the growth inhibition or cell death, and apoptosis through autophagy
- Kosmidis C., Sapalidis K., Koletsa T., Kosmidou M., Efthimiadis C. and Anthimidis G. (2018). Interferon-γ and Colorectal Cancer: an up-to date. Journal of Cancer, 9(2), 232-238.
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