IFNG

Official Full Name

interferon gamma

Organism

Homo sapiens

GeneID

3458

Background

This gene encodes a soluble cytokine that is a member of the type II interferon class. The encoded protein is secreted by cells of both the innate and adaptive immune systems. The active protein is a homodimer that binds to the interferon gamma receptor which triggers a cellular response to viral and microbial infections. Mutations in this gene are associated with an increased susceptibility to viral, bacterial and parasitic infections and to several autoimmune diseases. [provided by RefSeq, Dec 2015]

Synonyms

IFG; IFI; IMD69;

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Detailed Information

Interferon-γ (IFN-γ), the lone member of type II IFN family, has been found to associate with several pathophysiological processes in cancer, neurodegenerative diseases and hepatic dysfunction. It has been shown that IFN-γ exerts its function via regulating hundreds of genes including inflammatory signaling molecules, apoptosis and cell cycle regulators, and transcriptional activators.

IFN-γ signaling pathway

Previous evidences have shown that IFN-γ-mediates its diverse biological functions through activation of intercellular molecular signaling networks, mainly via JAK/STAT pathway (Figure 1). In canonical IFN-γ signaling, upon IFN-γ binding to IFN-γ receptor (IFNGR), the receptor’s subunits IFN-γ R1 and IFN-γ R2 oligomerize and transphosphorylate, activating the downstream regulator-associated Janus activated kinase (JAK)1 and JAK2. Furthermore, the activated JAKs phosphorylate and activate transducer and activator of transcription 1 (STAT1) in most cells and STAT3 in some cells. However, this step can be inhibited by physiological negative regulator suppressor of cytokine signaling 1 (SOCS1). Phosphorylated STAT1 homodimerizes into a complex, known as gamma-activated factor (GAF), which translocate to the nucleus and act as transcription factors through binding to gamma-activated site (GAS) elements present in the promoters of most interferon-stimulated genes (ISGs). Moreover, upon trans-activating by IFN-γ signaling, interferon-regulatory factor 1 (IRF1) binds to interferon-stimulated response element (ISRE) and leads to the transcription of multiple secondary response genes responsible for several immunomodulatory functions. In addition to JAK-STAT signaling pathway, other pathways such as MAP kinase, PI3K, JNK, CaMKII and NF-κB also involve in the biological actions of IFN-γ.

IFN-γ Figure 1. Interferon-gamma (IFN-γ) canonical signaling pathway. (Castro F, et al. 2018)

IFN-γ and tumor immune

Accumulation studies have demonstrated that IFN-γ plays dual roles in tumor immunity. It has been shown that the double-face of IFN-γ on both antitumor and protumor depends on the context of tumor specificity, IFN-γ-signaling intensity, and other microenvironment conditions (Figure 2).

IFN-γ Figure 2. Dual face of interferon-gamma (IFN-γ) in tumor immunity. (Castro F, et al. 2018)

Antitumorigenic effects

A number of studies have described the antitumor effects of IFN-γ through multiple processes. It has been shown that IFN-γ inhibits tumor proliferation via regulating the expression of cyclin-dependent kinase inhibitor 1 (p21) activated by STAT1 in tumor cells. Moreover, IFN-γ has been found to increase the expression of caspase-1, -3, -8 and enhance the secretion of FAS and FAS ligand and TNF-related apoptosis-inducing ligand, promoting tumor cells apoptosis. It also has been found that IFN-γ regulates necrotic death by influencing the activity of the serine–threonine kinase RIP1 to achieve its tumoricidal effects. Additionally, IFN-γ is implicated with the repression of angiogenesis and the impairment of endothelial cells, leading to tumor stroma ischemia and tumor rejection. Interestingly, IFN-γ is also involved in T cell, NK and NKT cell trafficking into the tumors by chemokine (C-X-C motif) ligand 9, CXCL10, and CXCL11 induction. Furthermore, several studies have revealed that IFN-γ is involved in macrophages tumoricidal activity and cancer immune surveillance via acting on the production of IL-12.

Protumorigenic effects

Contrary to the antitumorigenic effects, IFN-γ also has been found to exert protumorigenic effects including proliferative and antiapoptotic signals, as well as escape of the tumor cells from recognition and cytolysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Additionally, studies have described that IFN-γ might involve in the remodeling and repair of damaging cells, while on cells harboring oncogenic mutations, the same mechanisms might contribute to complete transformation. Moreover, it also has been found that IFN-γ is implicated with the of formation of immunosuppressive tumor microenvironment via triggering homeostatic response to limit inflammation and promotes tumor cells to produce immunosuppressive molecules, as well as recruiting immunosuppressive cells.

References:

Castro F, et al. Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Frontiers in Immunology, 2018, 9:847.
Mojic M, et al. The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion. International Journal of Molecular Sciences, 2018, 19(1):89.
Kulkarni A, et al. Interferon gamma: influence on neural stem cell function in neurodegenerative and neuroinflammatory disease. Clinical Medicine Insights: Pathology, 2016, 9: CPath. S40497.
Attallah A M, et al. Interferon-gamma is associated with hepatic dysfunction in fibrosis, cirrhosis, and hepatocellular carcinoma. J Immunoassay Immunochem, 2016, 37(6):597-610.

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