IL27 - interleukin 27 |Elisa - Clia - Antibody - Protein

Background

Interleukin 27 (IL-27) is a heterodimeric cytokine that belongs to the IL-12 cytokine family and plays a pivotal role in regulating immune responses. IL-27 is produced primarily by antigen-presenting cells (APCs), such as dendritic cells, macrophages, and monocytes, following activation by various pathogen-associated signals. Its primary function is to modulate T cell responses, particularly by promoting the differentiation of T helper 1 (Th1) cells while simultaneously limiting excessive inflammatory responses through immune suppression. This dual role positions IL-27 as a key regulator of both pro-inflammatory and anti-inflammatory immune responses.

IL-27 is composed of two distinct subunits: EBI3 (Epstein-Barr virus-induced gene 3) and p28, which together form the functional cytokine. IL-27 signals through a heterodimeric receptor composed of IL-27R (WSX-1) and gp130, activating a range of signaling pathways that control immune function, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The ability of IL-27 to regulate both inflammatory and regulatory responses makes it an important molecule in the context of autoimmune diseases, infection, cancer, and other immunological conditions.

Protein Structure

IL-27 is a heterodimer consisting of two protein subunits: EBI3 and p28.

EBI3 Subunit:

• EBI3 is a glycoprotein composed of 229 amino acids and belongs to the IL-12/IL-6 cytokine family. It shares structural similarity with IL-12 p40 and serves as a binding partner for both p28 (in IL-27) and p35 (in IL-12).
• The tertiary structure of EBI3 resembles a solenoid fold, typical of the IL-12 family, with several α-helices contributing to its interaction with the p28 subunit.

p28 Subunit:

• p28 is composed of 243 amino acids and is similar in structure to other cytokines in the IL-6/IL-12 family. It has a typical four-helix bundle topology, characteristic of the long-chain cytokine family, which enables it to engage with receptor components.
• The four-helix bundle consists of α-helices that are connected by loops, with disulfide bonds playing a role in maintaining structural integrity. The hydrophobic core of this structure allows stable receptor interaction.

Together, these subunits form a functional heterodimer. The heterodimeric nature of IL-27 allows it to engage its receptor complex efficiently, facilitating downstream signaling.

Classification and Subtypes

IL-27 belongs to the IL-12 cytokine family, which includes other heterodimeric cytokines such as IL-12, IL-23, and IL-35. These cytokines share similar structural features and play important roles in regulating immune responses, particularly in the context of infection and inflammation.

IL-27 does not have distinct subtypes, but it is part of the broader IL-12 family, which is classified based on its structural features and receptor usage.

• IL-12 (composed of p35 and p40)
• IL-23 (composed of p19 and p40)
• IL-35 (composed of p35 and EBI3)
• IL-27 (composed of p28 and EBI3)

The structural and functional similarities among these cytokines provide insight into their overlapping and distinct roles in immune regulation.

Function and Biological Significance

IL-27 has multiple roles in modulating the immune response, with both pro-inflammatory and anti-inflammatory functions. Its diverse effects are largely mediated through its interaction with the IL-27 receptor on target cells, including T cells, B cells, and innate immune cells.

Pro-inflammatory Functions:

Promotion of Th1 Responses:

• IL-27 is a potent inducer of Th1 cell differentiation by promoting the expression of T-bet, a transcription factor essential for Th1 development, and increasing the production of interferon-gamma (IFN-γ). This makes IL-27 an important cytokine in responses against intracellular pathogens such as viruses and intracellular bacteria.

Enhancement of Cytotoxic T Cells:

• IL-27 can enhance the activity of cytotoxic T lymphocytes (CTLs), promoting the elimination of infected or malignant cells. This has implications in both viral infections and tumor immunity.

Synergy with IL-12:

• IL-27 often works in concert with IL-12 to amplify Th1 responses, particularly in the early stages of immune responses. Together, these cytokines help initiate and sustain cell-mediated immunity.

Anti-inflammatory and Regulatory Functions:

Suppression of Th17 Cells:

• IL-27 has the ability to suppress the differentiation of Th17 cells, which are known for their role in chronic inflammation and autoimmune diseases. By inhibiting Th17 responses, IL-27 helps to control excessive inflammatory reactions and maintains immune homeostasis.

Induction of Tr1 Cells:

• One of the major anti-inflammatory roles of IL-27 is the induction of T regulatory type 1 (Tr1) cells, which are characterized by their ability to produce IL-10. Tr1 cells are involved in dampening immune responses and preventing tissue damage during chronic inflammation or infection.

Limiting Immune Pathology:

• IL-27 can act to limit immune-mediated damage in the context of chronic infections and autoimmune diseases. By promoting anti-inflammatory pathways, it prevents excessive tissue damage while allowing the immune system to control infection or inflammation.

Role in Innate Immunity:

• IL-27 can also act on innate immune cells, such as natural killer (NK) cells and macrophages, enhancing their antimicrobial functions while also regulating their inflammatory potential. In this way, IL-27 contributes to both the early and late phases of immune responses.

Clinical Issues

Due to its dual roles in both promoting and regulating immune responses, IL-27 has been implicated in a variety of clinical conditions.

Autoimmune Diseases:

Multiple Sclerosis (MS):

• IL-27 has been shown to limit the development of Th17 cells, which are central to the pathology of multiple sclerosis. Animal models suggest that IL-27 can ameliorate disease progression in MS by reducing inflammation and promoting regulatory immune responses.

Rheumatoid Arthritis (RA):

• In rheumatoid arthritis, IL-27 levels are elevated in the inflamed synovium, where it contributes to both pro-inflammatory and anti-inflammatory responses. While IL-27 promotes Th1 responses, it also limits the activity of Th17 cells, which are implicated in joint destruction. This dual role makes IL-27 a potential target for therapeutic intervention in RA.

Inflammatory Bowel Disease (IBD):

• IL-27 may play a protective role in Crohn’s disease and ulcerative colitis, where it suppresses Th17-driven inflammation. Studies suggest that enhancing IL-27 signaling could reduce chronic intestinal inflammation and improve disease outcomes.

Infectious Diseases:

• IL-27 plays a crucial role in immune responses to various viral and bacterial infections. It is particularly important in the early stages of infection, where it enhances Th1 responses and promotes the clearance of intracellular pathogens.
• However, in certain chronic infections, such as tuberculosis, IL-27 may limit protective immune responses by suppressing Th17 cells, leading to persistent infection. Balancing IL-27 activity is therefore crucial in managing infections.

Cancer:

• IL-27 has been implicated in tumor immunity, where it enhances the activity of cytotoxic T cells and NK cells. These effects are thought to contribute to the anti-tumor immune response, making IL-27 a potential therapeutic target for cancer immunotherapy.
• However, the role of IL-27 in cancer is complex, as it can also promote regulatory pathways that may limit effective anti-tumor immunity.

Summary

IL-27 is a heterodimeric cytokine with significant roles in both immune activation and immune regulation. Structurally composed of EBI3 and p28 subunits, IL-27 signals through a receptor complex involving IL-27R (WSX-1) and gp130, leading to activation of the JAK/STAT signaling pathway. It promotes Th1 differentiation, enhances cytotoxic T cell responses, and limits Th17-driven inflammation, thereby regulating the balance between pro-inflammatory and anti-inflammatory responses.

Clinically, IL-27 is involved in the pathogenesis of several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Its ability to limit excessive immune responses also makes it a candidate for treating chronic inflammatory diseases and cancer. Understanding the multifaceted roles of IL-27 is critical for developing new therapeutic strategies aimed at modulating immune responses in disease settings.