IFNA4 - interferon alpha 4 |Elisa - Clia - Antibody - Protein

Background

Interferon-alpha 4 (IFN-α4) belongs to the type I interferon family, which is a key group of cytokines produced primarily in response to viral infections. Type I interferons, including IFN-α4, play essential roles in the innate immune response, providing the body with its first line of defense against pathogens. The expression of IFN-α4 is primarily triggered by pathogen-associated molecular patterns (PAMPs), such as viral nucleic acids, which activate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs). IFN-α4 then exerts its antiviral effects through the activation of various downstream immune signaling pathways.

The IFN-α family includes more than 13 different subtypes, each encoded by a separate gene, with IFN-α4 being one of the less commonly studied but functionally significant subtypes. While all type I interferons share a similar mechanism of action, each subtype may have slightly different efficacy in stimulating immune responses and antiviral defenses.

The role of IFN-α4 in the immune system is broad, contributing not only to viral clearance but also to the regulation of immune responses, particularly influencing other immune cells such as natural killer (NK) cells, macrophages, and T lymphocytes. IFN-α4 is also involved in promoting antigen presentation, an essential process for the development of adaptive immunity. Furthermore, IFN-α4 has been studied in the context of cancer immunotherapy and autoimmune diseases, although its clinical application remains limited in comparison to other interferon subtypes, such as IFN-α2.

Protein Structure

The protein structure of IFN-α4 shares significant similarities with other members of the type I interferon family. IFN-α4 is a glycoprotein with a molecular weight of around 19-22 kDa. It is composed of approximately 165 amino acids, and like other type I interferons, it is rich in α-helices that are critical for its receptor-binding properties and downstream signaling.

Primary Structure:

• IFN-α4 is encoded by the IFNA4 gene, located on chromosome 9p21 in humans. The gene undergoes transcription and translation into a precursor polypeptide that includes a signal peptide at the N-terminus. This signal peptide is cleaved off during maturation, producing the mature IFN-α4 protein.

Secondary and Tertiary Structure:

• The secondary structure of IFN-α4 consists of five tightly packed α-helices arranged in a helical bundle. This conformation is a hallmark of type I interferons and is critical for its interaction with the interferon-alpha/beta receptor (IFNAR).
• The tertiary structure of IFN-α4 forms a compact, globular shape stabilized by disulfide bonds and hydrogen bonding within the α-helices. This structure allows IFN-α4 to engage both subunits of the IFNAR complex: IFNAR1 and IFNAR2.

Quaternary Structure:

• IFN-α4 functions as a monomer in its active form, although its interaction with the IFNAR receptor initiates receptor dimerization and signaling. This activation is the same mechanism utilized by other type I interferons.

Post-Translational Modifications:

• Like many cytokines, IFN-α4 undergoes glycosylation, particularly N-linked glycosylation, which impacts its biological activity, stability, and half-life in circulation. Glycosylation may also play a role in the immunogenicity of the protein when used therapeutically.

Classification and Subtypes

IFN-α4 is classified under the type I interferon family, a group of interferons that includes several subtypes of IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω. Within the IFN-α subfamily, there are at least 13 different subtypes in humans, each encoded by distinct genes but sharing considerable sequence homology (approximately 75-80% sequence similarity).

Although IFN-α4 is less studied compared to other subtypes like IFN-α2, it remains an important cytokine due to its ability to elicit robust antiviral responses. It is part of a larger group of IFN-α subtypes that can differ in their binding affinities to IFNAR, their efficacy in inducing ISGs, and their overall biological activity.

Function and Biological Significance

The biological functions of IFN-α4 align closely with those of other type I interferons, although with some differences in potency depending on the context and disease state.

Antiviral Activity:

• IFN-α4 plays a pivotal role in protecting cells against viral infections. Upon binding to IFNAR, it triggers the JAK-STAT signaling pathway, leading to the transcription of interferon-stimulated genes (ISGs). These ISGs encode proteins that inhibit viral replication, degrade viral RNA, and prevent the assembly and release of new virions. Prominent ISGs include OAS1, MxA, and PKR, all of which act to suppress viral activity.
• IFN-α4 is especially important in the context of early immune responses to viral infections, such as those caused by influenza, hepatitis viruses, and other RNA viruses.

Immunomodulation:

• Beyond its antiviral functions, IFN-α4 modulates the activity of various immune cells, including natural killer (NK) cells, dendritic cells, and T lymphocytes. It enhances the cytotoxic activity of NK cells, promotes the maturation of dendritic cells, and drives the differentiation of Th1 cells (T-helper 1), which are crucial for cellular immunity.
• IFN-α4 also increases the expression of MHC class I molecules, facilitating better antigen presentation and subsequent recognition by cytotoxic T lymphocytes (CTLs).

Antiproliferative and Antitumor Effects:

• IFN-α4, like other type I interferons, has antiproliferative properties, particularly relevant in the context of cancer. It can inhibit tumor cell growth by inducing cell cycle arrest and promoting apoptosis. Moreover, IFN-α4 enhances immune surveillance by increasing the recognition and destruction of cancerous cells by immune cells.

Regulation of Inflammation:

• IFN-α4 contributes to the regulation of inflammation by modulating the production of pro-inflammatory cytokines and chemokines. However, in certain cases, excessive or prolonged production of IFN-α4 can lead to chronic inflammation, contributing to the pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE).

Clinical Issues

Despite its potent antiviral and immunoregulatory effects, IFN-α4 is less commonly used in clinical settings compared to IFN-α2, which is the most widely used subtype in interferon therapy.

Viral Infections:

• IFN-α4, similar to other interferon subtypes, could theoretically be used to treat chronic viral infections such as hepatitis B and hepatitis C, although it has not been as widely tested in clinical trials for these conditions. Instead, IFN-α2 has been the primary subtype for these applications, largely due to its better-characterized safety and efficacy profiles.

Cancer Therapy:

• Type I interferons, including IFN-α4, have demonstrated some efficacy in the treatment of cancers such as melanoma, renal cell carcinoma, and chronic myelogenous leukemia (CML). The antiproliferative and pro-apoptotic effects of IFN-α4 could make it a candidate for cancer immunotherapy, although its use in this area is limited due to the availability of more effective and less toxic alternatives.

Side Effects:

• Like other interferons, IFN-α4 is associated with significant side effects, including flu-like symptoms (fever, fatigue, myalgia), and more severe complications such as myelosuppression, neuropsychiatric effects (e.g., depression), and autoimmune disorders. These side effects have limited the long-term use of interferons in clinical practice.

Autoimmunity:

• Chronic overproduction of IFN-α4 has been implicated in autoimmune diseases, particularly systemic lupus erythematosus (SLE). Elevated levels of type I interferons, including IFN-α4, are commonly found in SLE patients, where they contribute to B cell hyperactivation, the production of autoantibodies, and the perpetuation of chronic inflammation.

Summary

Interferon-alpha 4 (IFN-α4) is a member of the type I interferon family, with significant roles in antiviral defense, immune modulation, and tumor suppression. Structurally, IFN-α4 consists of α-helices that are critical for its interaction with the IFNAR receptor, triggering a cascade of immune signaling pathways, including the JAK-STAT pathway. Although less studied compared to other subtypes like IFN-α2, IFN-α4 contributes to the body’s ability to fight viral infections, modulate immune responses, and inhibit cancer growth. However, its clinical utility is limited due to the side effects associated with interferon therapies, and more research is needed to fully understand its potential in disease treatment.