IFNG - interferon gamma |Elisa - Clia - Antibody - Protein

Background

Interferon Gamma (IFN-γ) is a critical cytokine that plays a pivotal role in the immune system, particularly in the defense against intracellular pathogens such as viruses, bacteria, and parasites. It is the sole member of the Type II interferon family, differentiating it from Type I interferons (like IFN-α and IFN-β). Produced primarily by natural killer (NK) cells and T lymphocytes, IFN-γ serves as a bridge between the innate and adaptive immune responses.

IFN-γ is essential in coordinating the immune response by activating macrophages, enhancing antigen presentation, and promoting the differentiation of T cells. It acts as a key regulator of immune surveillance, inflammation, and cellular immunity. IFN-γ is particularly well-known for its role in macrophage activation, a process critical in controlling infections and tumor surveillance. Additionally, IFN-γ is a potent activator of major histocompatibility complex (MHC) expression, increasing the ability of immune cells to detect and present antigens.

Given its critical role in immune modulation, IFN-γ has been implicated in a wide variety of clinical conditions, including autoimmune diseases, infectious diseases, and cancer. Understanding the structure, function, and regulation of IFN-γ is crucial for harnessing its potential in therapeutic applications.

Protein Structure

IFN-γ is a homodimeric glycoprotein composed of two identical subunits, each containing 143 amino acids, resulting in a combined molecular weight of approximately 20-25 kDa. The structure of IFN-γ differs significantly from the Type I interferons (IFN-α/β), reflecting its unique biological properties.

Primary Structure:

• IFN-γ is encoded by the IFNG gene, located on chromosome 12q15 in humans. It is initially synthesized as a precursor peptide that undergoes post-translational modifications before being secreted.
• The mature form of IFN-γ contains several conserved amino acid sequences, including cysteine residues that form disulfide bonds crucial for maintaining its stability and dimerization.

Secondary and Tertiary Structure:

• IFN-γ is characterized by a four α-helical bundle structure, which is a typical feature of cytokines. This bundle forms the core structure of the protein, providing a stable scaffold for receptor binding.
• The homodimeric form is stabilized through disulfide bridges and non-covalent interactions, which enhance its biological activity and stability. Each monomer contributes to the binding interface with its receptor.

Post-Translational Modifications:

• Glycosylation occurs on specific residues of IFN-γ, which is critical for its secretion, stability, and bioactivity. The glycosylation sites are involved in regulating the protein's interaction with its receptor.
• Phosphorylation may also influence IFN-γ’s interactions and downstream signaling pathways, though this is less well characterized compared to glycosylation.

Classification and Subtypes

Unlike Type I interferons, which have several subtypes (e.g., IFN-α has over a dozen isoforms), IFN-γ exists as a single, unique cytokine. It is the only member of the Type II interferon family.

• Type I Interferons include IFN-α, IFN-β, IFN-κ, and others, which primarily act in antiviral responses.
• Type II Interferon (i.e., IFN-γ) primarily functions in activating the adaptive immune response and driving cellular immunity against intracellular pathogens.

Thus, while IFN-γ lacks subtypes, its effects are highly versatile, owing to its ability to regulate a wide variety of immune processes.

Function and Biological Significance

IFN-γ has a broad range of biological functions, most notably its role in immune regulation and host defense.

Macrophage Activation:

• One of the hallmark functions of IFN-γ is the activation of macrophages, which enhances their ability to phagocytose pathogens, produce reactive oxygen species (ROS), and secrete pro-inflammatory cytokines. Activated macrophages are crucial for controlling infections with intracellular pathogens such as Mycobacterium tuberculosis and Listeria monocytogenes.
• IFN-γ activates macrophages through the JAK-STAT pathway, particularly STAT1, which drives the expression of genes related to pathogen recognition and killing.

Enhancement of Antigen Presentation:

• IFN-γ enhances the expression of both MHC class I and II molecules on antigen-presenting cells (APCs) such as dendritic cells and macrophages. This process is critical for the presentation of antigens to CD8+ cytotoxic T cells and CD4+ helper T cells, thereby enhancing immune recognition and the clearance of infected or malignant cells.

T Cell Differentiation and Immune Modulation:

• Th1 Cell Differentiation: IFN-γ is critical for promoting the differentiation of naïve T helper cells (Th0) into Th1 cells, which are responsible for mediating cellular immunity. This makes IFN-γ essential for responses against intracellular bacteria and viruses.
• It also inhibits Th2 cell differentiation, which is associated with humoral immunity and allergic responses, thus modulating the balance between cellular and humoral immune responses.

Antiviral and Antitumor Effects:

• While Type I interferons are more directly involved in the antiviral response, IFN-γ contributes by enhancing the immune system's ability to identify and destroy virally infected cells through the upregulation of MHC molecules and the activation of NK cells and T cells.
• IFN-γ is also critical for the anti-tumor immune response. It activates cytotoxic T lymphocytes (CTLs) and enhances the capacity of immune cells to kill tumor cells by increasing the expression of antigens on the tumor surface.

Clinical Issues

Therapeutic Applications:

Given its wide-ranging effects on the immune system, IFN-γ has been explored as a therapeutic agent in several conditions:

• Chronic Granulomatous Disease (CGD): IFN-γ is approved for use in patients with CGD, a genetic disorder where immune cells cannot produce the reactive oxygen species needed to kill certain pathogens. IFN-γ helps by enhancing macrophage activity and compensating for this deficiency.
• Severe Infections: IFN-γ has been used to treat severe infections like atypical mycobacterial infections in immunocompromised patients, where the regular immune system response is insufficient.

Autoimmune Diseases:

Although IFN-γ plays a protective role in infections, its overproduction or dysregulation can contribute to the pathogenesis of autoimmune diseases:

• Multiple Sclerosis (MS): Elevated levels of IFN-γ are associated with MS flares, where an excessive Th1 response contributes to the immune-mediated attack on the central nervous system.
• Rheumatoid Arthritis (RA): IFN-γ can exacerbate joint inflammation in RA by promoting the production of pro-inflammatory cytokines and enhancing immune cell infiltration into the synovium.

Infectious Diseases:

IFN-γ is crucial for immune responses to various infections, particularly tuberculosis. Individuals with defects in IFN-γ signaling pathways are highly susceptible to infections by intracellular bacteria and mycobacteria, underscoring its role in protective immunity.

Cancer Immunotherapy:

IFN-γ’s ability to enhance tumor antigen presentation and cytotoxic T cell activity has led to its investigation as a potential cancer immunotherapy. While it has shown promise in preclinical studies, its clinical efficacy has been limited due to its short half-life and potential for inducing autoimmune side effects when administered systemically.

Inflammatory and Infectious Conditions:

Dysregulated production of IFN-γ has also been implicated in inflammatory conditions, such as systemic lupus erythematosus (SLE), where excessive activation of the immune system leads to tissue damage.

Summary

Interferon Gamma (IFN-γ) is a crucial cytokine in both the innate and adaptive immune responses. Its structure as a homodimeric protein with a four-helix bundle enables it to interact with its receptor and activate the JAK-STAT signaling pathway, which in turn leads to a wide array of immune-regulating effects.

IFN-γ is produced mainly by NK cells and T lymphocytes and is responsible for macrophage activation, enhancement of antigen presentation, T cell differentiation, and the modulation of immune responses against pathogens and tumors.

Its role in clinical settings is diverse, from treating chronic granulomatous disease to being implicated in the pathology of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Additionally, IFN-γ plays a role in cancer immunotherapy, although its potential in this domain is still being actively researched.

In summary, IFN-γ is indispensable for immune regulation, particularly in the control of intracellular pathogens and tumor surveillance, but its clinical application requires careful management due to its broad immune-activating properties.