IFNL3 - interferon lambda 3 |Elisa - Clia - Antibody - Protein

Background

Interferon Lambda 3 (IFNL3), also known as IL-28B, is a cytokine that belongs to the Type III interferon family, which plays a critical role in the innate immune system, particularly in antiviral defense. IFNL3, like other Type III interferons, activates signaling pathways that result in the expression of interferon-stimulated genes (ISGs), creating an antiviral state within cells. IFNL3 primarily targets epithelial cells, such as those lining the respiratory tract, gastrointestinal tract, and liver, which are common entry points for viral infections.

The discovery of IFNL3 and its genetic variations has been of significant interest, especially due to its role in the treatment and clearance of hepatitis C virus (HCV) infections. Genetic polymorphisms in the IFNL3 gene are strong predictors of treatment response in HCV patients, influencing outcomes of both spontaneous viral clearance and antiviral therapy. This connection has made IFNL3 a focus of research in viral infections, where immune response to chronic infections is crucial.

IFNL3 exerts similar antiviral functions to Type I interferons (e.g., IFN-α and IFN-β), but it has a more restricted target profile, predominantly acting on epithelial and barrier cells rather than affecting all nucleated cells, as is the case with Type I interferons. This localized action helps in reducing systemic side effects, such as those observed in broad-spectrum interferon treatments.

Protein Structure

The IFNL3 protein is a glycoprotein with a molecular weight of approximately 22-24 kDa, and like other members of the Type III interferon family, it has a four α-helical bundle structure. The α-helical structure is important for its interaction with receptors and its biological function.

Primary Structure:

• The IFNL3 gene is located on chromosome 19 (19q13.13) in humans, closely clustered with the genes for IFNL1 (IL-29) and IFNL2 (IL-28A).
• The IFNL3 gene encodes a protein composed of approximately 195 amino acids, including a signal peptide at the N-terminal end, which is cleaved during protein processing to yield the mature cytokine.

Secondary and Tertiary Structure:

• IFNL3 adopts the canonical four α-helical bundle structure found in most cytokines, including other interferons. These helices are arranged in an antiparallel fashion, creating a compact and stable structure.
• This structural organization is essential for IFNL3’s interaction with its receptor, as it helps maintain the correct spatial orientation for binding.

Post-Translational Modifications:

• Glycosylation occurs at specific asparagine residues in the mature IFNL3 protein. Glycosylation is critical for protein stability, solubility, and enhancing interactions with its receptor.
• The presence of disulfide bonds between specific cysteine residues in the protein provides additional stability to its structure, ensuring proper folding and function.

Classification and Subtypes

IFNL3 is part of the Type III interferon family, which also includes:

• IFNL1 (IL-29)
• IFNL2 (IL-28A)
• IFNL4 (a recently discovered member with less well-characterized functions)

These cytokines are grouped together due to their shared receptor system and structural similarities. Type III interferons, including IFNL3, signal through a receptor complex composed of two subunits:

• IFNLR1 (interferon lambda receptor 1): This receptor is specific to the Type III interferon family.
• IL-10R2 (interleukin-10 receptor 2): This subunit is shared with other cytokines, including IL-10, IL-22, and IL-26.

The interaction of IFNL3 with these receptors triggers intracellular signaling cascades that lead to the expression of antiviral and immune-modulatory genes.

While IFNL3, IFNL1, and IFNL2 share high sequence homology and similar biological activities, IFNL3 has garnered particular interest due to its significant role in predicting treatment outcomes for viral infections like HCV.

Function and Biological Significance

Antiviral Defense:

The primary role of IFNL3 is to induce antiviral immunity, especially at mucosal and epithelial surfaces. Upon binding to its receptor complex (IFNLR1/IL-10R2), IFNL3 activates the JAK-STAT signaling pathway, leading to the phosphorylation of STAT1 and STAT2. This promotes the formation of the ISGF3 (interferon-stimulated gene factor 3) complex, which translocates to the nucleus and induces the transcription of interferon-stimulated genes (ISGs).

ISGs encode proteins with various antiviral functions, including:

• MxA protein, which inhibits viral replication.
• PKR (protein kinase R), which halts protein synthesis in infected cells.
• OAS (2′,5′-oligoadenylate synthetase), which activates RNase L to degrade viral RNA.

These antiviral responses effectively limit viral replication, preventing the spread of infection within the host.

Role in Hepatitis C Virus (HCV) Clearance:

A key biological significance of IFNL3 lies in its role in the immune response to HCV. Genetic polymorphisms near the IFNL3 gene, particularly the rs12979860 and rs8099917 variants, are associated with spontaneous clearance of HCV and a better response to interferon-based therapy. Individuals with the favorable allele tend to have a more robust IFNL3-mediated antiviral response, leading to improved viral clearance.

Immune Modulation:

Besides its antiviral effects, IFNL3 has roles in modulating immune responses. Unlike Type I interferons, which act broadly on almost all nucleated cells, IFNL3 primarily affects epithelial cells, providing localized immune protection without causing the systemic inflammation and autoimmune side effects often seen with Type I interferon treatments. This makes it an appealing candidate for therapeutic applications where minimizing immune-mediated damage is critical.

Clinical Issues

Therapeutic Potential:

IFNL3’s selective activity on epithelial surfaces makes it a potential therapeutic agent for a range of viral infections, including:

• Hepatitis C Virus (HCV): As mentioned, genetic variations in IFNL3 predict treatment response in HCV patients. IFNL3-based therapies could be optimized to enhance antiviral immunity in HCV-infected individuals, especially in combination with direct-acting antiviral drugs.
• Respiratory Infections: IFNL3’s ability to target respiratory epithelial cells makes it a candidate for treating viruses such as influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 (responsible for COVID-19). Early studies suggest that IFNL3 can reduce viral replication in the lungs without causing the severe inflammatory responses seen with Type I interferons.

Autoimmune Concerns:

While Type III interferons are less likely to cause autoimmune diseases compared to Type I interferons, there remains some concern about the potential for autoimmune activation in certain individuals, particularly those with underlying immune dysregulation. Studies are ongoing to evaluate the long-term safety of IFNL3 in clinical applications.

Polymorphisms and Genetic Influence:

Genetic variations near the IFNL3 gene are a major determinant of the body's ability to clear certain viral infections. The most well-known of these polymorphisms is rs12979860, which strongly influences outcomes in HCV infection. Individuals with the CC genotype at this locus have a higher likelihood of spontaneously clearing HCV and responding to interferon-based therapy, whereas those with the TT genotype have poorer outcomes.

Summary

Interferon Lambda 3 (IFNL3), a member of the Type III interferon family, is a cytokine involved in the innate immune response, particularly against viral infections at epithelial surfaces. Structurally, it adopts a four α-helical bundle and signals through the IFNLR1/IL-10R2 receptor complex, activating the JAK-STAT pathway to induce antiviral gene expression.

IFNL3 is of significant clinical interest due to its role in HCV clearance and its potential for therapeutic use in viral respiratory infections like COVID-19 and influenza. Genetic polymorphisms near the IFNL3 gene are key predictors of treatment response in HCV, with individuals possessing favorable genetic variants showing better outcomes.

While IFNL3’s restricted receptor distribution reduces the risk of systemic side effects and autoimmune complications, more research is needed to fully understand its long-term safety and effectiveness in various therapeutic settings. Nevertheless, IFNL3 represents a promising tool in the fight against viral infections, particularly those that affect epithelial barriers, making it an exciting area of ongoing research in immunology and antiviral therapy.