IFNL1 - interferon lambda 1 |Elisa - Clia - Antibody - Protein

Background

Interferon Lambda 1 (IFNL1), also known as IL-29, is a member of the Type III interferon family, which includes IFNL1, IFNL2 (IL-28A), and IFNL3 (IL-28B), and more recently discovered IFNL4. These cytokines are involved in antiviral immunity and have significant overlap in function with Type I interferons (such as IFN-α and IFN-β), but with distinct cellular targeting. IFNL1 plays a key role in the innate immune response, especially in protecting epithelial barriers, such as those found in the lungs, intestines, and liver, from viral infections.

Unlike Type I interferons, which have broad activity across multiple cell types, Type III interferons like IFNL1 act primarily on cells that express the interferon lambda receptor (IFNLR1), which is most commonly found on epithelial cells and some immune cells like dendritic cells. This targeted action is thought to provide a more localized antiviral defense while minimizing the systemic inflammatory responses often seen with Type I interferons.

IFNL1 has gained significant attention for its role in protecting mucosal surfaces from viral infections, particularly respiratory viruses such as influenza and SARS-CoV-2, the virus responsible for COVID-19. Its restricted receptor expression pattern makes it an attractive therapeutic target because it offers antiviral activity with a reduced risk of inducing widespread inflammation and autoimmune responses.

Protein Structure

IFNL1 is a glycoprotein with a molecular weight of approximately 22-24 kDa. Like other cytokines, its structure is critical for its receptor interaction and biological activity. Interferon lambda proteins are composed of several structural features typical of the cytokine family.

Primary Structure:

• The IFNL1 gene is located on chromosome 19q13.13 in humans. It encodes a precursor protein that undergoes post-translational modifications to become functionally active.
• The mature IFNL1 protein consists of 200 amino acids, including a signal peptide that is cleaved during protein maturation.

Secondary and Tertiary Structure:

• IFNL1, like other members of the Type III interferon family, adopts a four α-helical bundle structure, which is typical of cytokines. This structure is critical for maintaining the protein's stability and for interacting with its receptor.
• The helices are connected by loops and are arranged in an antiparallel configuration, forming a compact, globular structure. This helical bundle is a hallmark of cytokine proteins and is critical for the specific binding of IFNL1 to its receptor.

Post-Translational Modifications:

• Glycosylation: Like many cytokines, IFNL1 is glycosylated at specific asparagine residues. Glycosylation is essential for its stability, solubility, and bioactivity. It also aids in the proper folding of the protein and can influence the receptor binding affinity.
• Disulfide bonds are present, which stabilize the tertiary structure of the protein, ensuring its correct folding and functional state.

Classification and Subtypes

IFNL1 belongs to the Type III interferon family, which consists of:

• IFNL1 (IL-29)
• IFNL2 (IL-28A)
• IFNL3 (IL-28B)
• IFNL4 (recently discovered and less well characterized)

These cytokines are grouped based on their use of the interferon lambda receptor (IFNLR1) in combination with the IL-10R2 subunit for signaling. Although structurally related to Type I interferons, they exhibit different receptor usage and cellular targeting, particularly favoring epithelial tissues. This makes them functionally distinct despite the shared antiviral properties.

Function and Biological Significance

IFNL1 plays a pivotal role in the antiviral immune response, particularly in protecting mucosal surfaces, which are the primary entry points for many viruses. Its primary functions include:

Antiviral Defense:

• IFNL1 triggers antiviral responses by binding to its specific receptor complex, composed of IFNLR1 and IL-10R2, leading to the activation of the JAK-STAT signaling pathway. This results in the transcription of interferon-stimulated genes (ISGs), which help limit viral replication and spread.
• The antiviral effects of IFNL1 are similar to those of Type I interferons but are more restricted to epithelial cells, such as those lining the respiratory and gastrointestinal tracts. This localized action is crucial for the containment of viral infections at these barriers without causing widespread systemic inflammation.

Mucosal Immunity:

• The primary targets of IFNL1 are epithelial cells. By inducing antiviral states in these cells, IFNL1 helps to prevent the entry and replication of viruses that attempt to breach mucosal surfaces.
• In the respiratory tract, IFNL1 is highly effective against influenza, RSV (respiratory syncytial virus), and coronaviruses, including SARS-CoV-2. In the gastrointestinal tract, it provides defense against enteric viruses like rotavirus and norovirus.

Modulation of Immune Responses:

• Unlike Type I interferons, IFNL1 has a more moderate inflammatory profile. While it enhances the antiviral state of epithelial cells, it does not trigger a strong inflammatory response, which is beneficial for limiting tissue damage.
• IFNL1 also acts on dendritic cells and enhances the presentation of viral antigens to T cells, supporting the development of adaptive immune responses while avoiding excessive inflammation.

Clinical Issues

Therapeutic Potential:

Due to its targeted action on epithelial cells, IFNL1 is being studied as a therapeutic agent for various viral infections. Its ability to restrict viral replication while minimizing inflammation makes it an attractive candidate for respiratory and gastrointestinal viral infections.

• COVID-19: IFNL1 has garnered attention as a potential treatment for COVID-19 due to its ability to inhibit SARS-CoV-2 replication in respiratory epithelial cells. Clinical trials are ongoing to determine its effectiveness in reducing viral load and improving outcomes in patients.
• Hepatitis: IFNL1 is also being investigated in the treatment of chronic viral hepatitis, particularly hepatitis B and hepatitis C. Its targeted action on the liver makes it a promising therapeutic option for reducing viral replication and disease progression without the adverse side effects of systemic inflammation.

Autoimmune Conditions:

Given its potent antiviral effects, the use of IFNL1 in certain individuals could theoretically contribute to autoimmune conditions, although its lower inflammatory profile compared to Type I interferons makes this less of a concern. However, there is ongoing research to better understand its long-term effects, especially in the context of chronic viral infections.

Resistance Mechanisms:

In certain viral infections, viruses can develop mechanisms to evade the antiviral effects of interferons, including IFNL1. For example, viruses like hepatitis B and HIV have developed strategies to suppress interferon signaling, which complicates the therapeutic use of IFNL1 in treating these infections.

Summary

Interferon Lambda 1 (IFNL1) is a key player in the innate immune response, particularly in mucosal immunity. As a member of the Type III interferon family, IFNL1 shares functional similarities with Type I interferons, such as IFN-α and IFN-β, but with a more restricted target profile. Its action is primarily focused on epithelial cells, offering antiviral protection at mucosal surfaces without the excessive inflammation that can be triggered by other types of interferons.

Structurally, IFNL1 is a glycoprotein with a four α-helical bundle, essential for its interaction with the IFNLR1/IL-10R2 receptor complex. It activates the JAK-STAT signaling pathway, leading to the expression of interferon-stimulated genes that inhibit viral replication and spread. The unique receptor distribution for IFNL1 provides targeted antiviral protection to epithelial tissues in the lungs, intestines, and liver, making it highly effective against respiratory and gastrointestinal viruses.

Clinically, IFNL1 holds great promise as a therapeutic agent for viral infections like COVID-19, hepatitis, and other diseases where mucosal surfaces are the primary site of infection. Its ability to induce a localized antiviral response without causing systemic inflammation makes it a valuable tool in antiviral therapies. However, further research is needed to understand its long-term effects and potential in preventing or treating chronic viral infections.