IFNA2 - interferon alpha 2 |Elisa - Clia - Antibody - Protein

Background

Interferon-alpha 2 (IFN-α2) is a type I interferon, which plays a crucial role in the innate immune response and is primarily involved in the defense against viral infections. IFN-α2 is secreted by leukocytes, especially plasmacytoid dendritic cells (pDCs), in response to viral infections, bacterial pathogens, and certain cancers. IFN-α2 has broad antiviral, antiproliferative, and immunomodulatory activities, which are fundamental for initiating the immune response and shaping subsequent adaptive immune responses.

Type I interferons, including IFN-α2, act as first responders to pathogen-associated molecular patterns (PAMPs), such as viral RNA and DNA. Once produced, they activate signaling pathways that induce the transcription of hundreds of interferon-stimulated genes (ISGs), whose products inhibit viral replication, promote apoptosis of infected cells, and enhance immune cell recruitment and activation.

IFN-α2, one of the best-studied interferon subtypes, has been widely used in clinical settings, particularly for the treatment of viral infections such as hepatitis B and hepatitis C, and in certain cancers like melanoma. However, the clinical use of IFN-α2 is often accompanied by significant side effects, such as flu-like symptoms and immune dysregulation, complicating its therapeutic application.

Protein Structure

Interferon-alpha 2 (IFN-α2) is a glycoprotein that consists of approximately 165 amino acids and has a molecular weight of around 19.2 kDa. Its structure is highly conserved among type I interferons, characterized by a specific arrangement of α-helices essential for its biological activity.

Primary Structure:

• IFN-α2 is encoded by the IFNA2 gene, located on chromosome 9 in humans. This gene is transcribed and translated into a precursor form, which includes a signal peptide that directs the protein to the secretory pathway. The signal peptide is cleaved to generate the mature IFN-α2 protein.

Secondary Structure:

• The secondary structure of IFN-α2 is dominated by five α-helices, with the helices connected by short loops. This helical configuration provides the stability and functional specificity required for receptor binding and activation of downstream signaling pathways.

Tertiary Structure:

• The tertiary structure of IFN-α2 consists of a tightly packed bundle of α-helices, which form a compact, globular shape. This structure is essential for its interaction with the interferon-alpha receptor (IFNAR). IFN-α2 engages with two subunits of IFNAR, IFNAR1 and IFNAR2, triggering signal transduction.

Quaternary Structure:

• IFN-α2 functions as a monomer and does not require dimerization for its activity. However, its biological activity is dependent on binding to the heterodimeric IFNAR complex, which initiates downstream signaling.

Post-Translational Modifications:

• IFN-α2 undergoes glycosylation, which influences its stability, bioavailability, and immune function. The presence of N-linked glycosylation sites enhances the protein’s circulatory half-life and receptor interactions. Additionally, some studies have indicated that glycosylation can modulate its immunogenicity and activity in clinical settings.

Classification and Subtypes

IFN-α2 is part of the type I interferon family, which includes multiple IFN-α subtypes, along with IFN-β, IFN-ω, IFN-κ, and others. Among the IFN-α subtypes, IFN-α2 is further divided into three variants, based on slight differences in their amino acid sequences:

1. IFN-α2a
2. IFN-α2b
3. IFN-α2c

These variants exhibit very similar biological properties, but minor variations in their amino acid sequences may affect receptor binding affinity and the efficiency of antiviral and immunomodulatory activities. IFN-α2b is the most widely used clinical subtype, particularly in the treatment of viral infections and cancers.

Function and Biological Significance

The primary functions of IFN-α2 revolve around its antiviral, antiproliferative, and immunomodulatory effects:

Antiviral Activity:

• IFN-α2 is rapidly produced in response to viral infections. Upon secretion, it binds to the IFNAR receptor on neighboring cells, initiating the JAK-STAT signaling pathway. This leads to the induction of ISGs, which encode proteins that interfere with various stages of the viral life cycle, including viral replication, transcription, and assembly. Key ISGs activated by IFN-α2 include MxA, OAS1, and PKR, which mediate direct antiviral effects by degrading viral RNA or inhibiting translation.

Antiproliferative Effects:

• IFN-α2 exerts antiproliferative effects, particularly on tumor cells. By inducing cell cycle arrest and promoting apoptosis, IFN-α2 can inhibit tumor growth. It also enhances the expression of MHC class I molecules, improving the immune system’s ability to recognize and destroy cancer cells. This is a key mechanism through which IFN-α2 mediates its antitumor effects in cancer immunotherapy.

Immune Modulation:

• IFN-α2 plays a crucial role in regulating immune responses. It activates natural killer (NK) cells, enhancing their cytotoxic activity against infected or transformed cells. IFN-α2 also modulates the activity of macrophages and dendritic cells, promoting their maturation and ability to present antigens. Additionally, IFN-α2 influences the differentiation of T helper 1 (Th1) cells, driving the adaptive immune response towards cellular immunity, which is essential for clearing intracellular pathogens.

Role in Inflammation and Autoimmunity:

• IFN-α2 can contribute to chronic inflammation and autoimmunity under certain conditions. Its ability to promote antigen presentation, increase cytokine production, and activate immune cells can lead to immune system hyperactivity. In autoimmune diseases like systemic lupus erythematosus (SLE), elevated levels of IFN-α2 have been associated with increased autoantibody production and chronic inflammation.

Clinical Issues

IFN-α2 has been extensively studied and used clinically for several decades. However, its therapeutic applications are often accompanied by significant side effects, which limit its long-term use.

Viral Infections:

• IFN-α2 has been used in the treatment of chronic hepatitis B and hepatitis C infections. Although IFN-α2 was once a cornerstone of antiviral therapy, newer direct-acting antiviral agents (DAAs) have largely replaced interferon-based treatments for hepatitis C due to their better efficacy and fewer side effects.

Cancer Therapy:

• IFN-α2, particularly IFN-α2b, has been employed in the treatment of various cancers, including melanoma, renal cell carcinoma, and hairy cell leukemia. The antitumor effects of IFN-α2 arise from its ability to activate immune responses and inhibit tumor cell proliferation. However, the therapeutic use of IFN-α2 is often limited by its systemic toxicity, including flu-like symptoms, fatigue, and neuropsychiatric effects.

Side Effects and Toxicity:

• Patients undergoing IFN-α2 therapy frequently experience flu-like symptoms such as fever, chills, muscle aches, and fatigue. More severe side effects can include depression, myelosuppression, thyroid dysfunction, and autoimmune conditions. Long-term therapy with IFN-α2 is associated with bone marrow suppression, leading to anemia, neutropenia, and thrombocytopenia.

Autoimmune Diseases:

• IFN-α2 has been implicated in the pathogenesis of several autoimmune diseases, particularly SLE. The chronic overproduction of type I interferons, including IFN-α2, is thought to drive autoimmunity by enhancing the activation of autoreactive immune cells and increasing the production of autoantibodies. Elevated IFN-α2 levels have been correlated with disease severity in SLE patients.

Summary

Interferon-alpha 2 (IFN-α2) is a type I interferon with broad antiviral, immunomodulatory, and antiproliferative activities. It plays a central role in the innate immune response to viral infections and tumor surveillance. IFN-α2 exerts its effects by binding to the IFNAR receptor and activating the JAK-STAT signaling pathway, leading to the transcription of ISGs that inhibit viral replication and promote immune cell activation.

Structurally, IFN-α2 is a glycoprotein composed of α-helices, which form a compact, globular structure necessary for receptor binding. IFN-α2 has multiple clinically relevant subtypes, including IFN-α2a, IFN-α2b, and IFN-α2c, with IFN-α2b being the most widely used in therapeutic applications.

Clinically, IFN-α2 has been used to treat viral infections like hepatitis and certain cancers. However, its use is limited by side effects, including flu-like symptoms and the potential for inducing autoimmune conditions. Despite these challenges, IFN-α2 remains a key molecule in immunology and has paved the way for newer therapeutic strategies targeting viral and malignant diseases.