IL32 - interleukin 32 |Elisa - Clia - Antibody - Protein

Background

Interleukin 32 (IL-32) is a relatively newly discovered pro-inflammatory cytokine, originally identified in 2005. It is unique because it does not belong to the classical cytokine families, such as the IL-6 or IL-1 families, and its function is primarily associated with the regulation of inflammation. IL-32 is produced by a variety of cell types, including T cells, natural killer (NK) cells, monocytes, macrophages, fibroblasts, epithelial cells, and endothelial cells, underscoring its broad role in immune regulation.

IL-32 expression is induced by other cytokines such as IFN-γ (interferon-gamma), IL-12, IL-18, and TNF-α. Its expression is also elevated in response to pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS) found on bacterial surfaces, signifying its role in innate immune responses to infection.

IL-32 is implicated in a variety of chronic inflammatory diseases, including autoimmune disorders, cancer, atherosclerosis, and infectious diseases. Its potent ability to induce other pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, and IL-8 highlights its significance in amplifying immune responses.

Protein Structure

IL-32 is a non-glycosylated protein and exists in multiple isoforms due to alternative splicing of its mRNA. These isoforms include IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, and IL-32θ. Among these, IL-32γ is considered the most biologically active isoform and is often used in experimental studies.

Primary Structure:

• The IL-32 gene is located on chromosome 16 in humans, and it encodes a protein of approximately 131-234 amino acids, depending on the isoform.
• The different isoforms are produced through alternative splicing, which results in different protein lengths and functions.

Secondary and Tertiary Structure:

• IL-32 is classified as a four-helix bundle protein, similar to other cytokines. Its structure includes alpha-helical regions that facilitate its interaction with various protein partners and receptors.
• The absence of glycosylation and the relative lack of structural information (compared to more classical cytokines) suggest that IL-32 may rely more on protein-protein interactions rather than direct receptor-ligand binding for its activity.

Receptor Interaction:

• IL-32 does not bind to a specific cell surface receptor in the same manner as other cytokines like IL-6 or IL-1. Instead, its activity is mediated through interactions with intracellular molecules, including protein kinase C (PKC) and Nuclear Factor-kB (NF-kB) pathways.
• While there is no identified unique receptor for IL-32, it is known to exert its biological effects through TLR4 (Toll-like receptor 4) and caspase-1-dependent signaling, as well as macrophage and monocyte activation.

Classification and Subtypes

IL-32 does not belong to any classical cytokine family such as the IL-1 or IL-6 families, making it a unique pro-inflammatory cytokine. However, IL-32 exists in multiple isoforms generated by alternative splicing:

• IL-32α: The smallest isoform, with moderate biological activity.
• IL-32β: A slightly larger isoform, which retains most of the functions of IL-32α but with enhanced activity.
• IL-32γ: The most active isoform with strong pro-inflammatory effects.
• IL-32δ: Less studied, but thought to have moderate activity.
• IL-32ε, IL-32ζ, and IL-32θ: These isoforms have been less characterized in terms of function and expression but likely contribute to immune regulation in specific tissues or pathological contexts.

Function and Biological Significance

IL-32 plays a significant role in inflammation and immune responses through the induction of pro-inflammatory cytokines and other immune-regulating molecules. Its primary functions are associated with pathogen defense, immune cell activation, and amplifying inflammation in chronic diseases. Some key functions of IL-32 include:

Induction of Pro-inflammatory Cytokines:

• IL-32 is a potent inducer of other pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8, and IFN-γ, all of which play critical roles in acute and chronic inflammation. This positions IL-32 as a key amplifier of the immune response, especially during infection and inflammatory diseases.

Activation of Innate Immune Cells:

• IL-32 is produced by monocytes and macrophages, and it stimulates these cells to produce other inflammatory mediators. It can also act on natural killer (NK) cells, dendritic cells, and neutrophils, enhancing their cytokine production and immune activity.
• IL-32 is involved in the activation of macrophages and their polarization toward an M1 phenotype, which is associated with pro-inflammatory responses and microbicidal activity.

Induction of Apoptosis and Pyroptosis:

• IL-32 plays a role in caspase-1-dependent pathways, which can lead to pyroptosis (a form of programmed cell death linked to inflammation) in infected cells. This allows for the clearance of intracellular pathogens.

Pathogen Defense:

• IL-32 is implicated in the body’s defense against various bacterial, viral, and fungal pathogens. It has been shown to activate immune responses against pathogens such as Mycobacterium tuberculosis, HIV, and influenza viruses.

Regulation of Chronic Inflammation:

• In diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, IL-32 is significantly upregulated, driving chronic inflammation and tissue damage. IL-32 may act both as a mediator of immune cell recruitment and as a direct modulator of inflammation within the affected tissues.

Clinical Issues

IL-32 has been linked to various chronic inflammatory diseases and immune-related conditions. The high levels of IL-32 observed in several autoimmune disorders, infectious diseases, and cancers suggest that IL-32 plays a pivotal role in modulating immune responses in both acute and chronic settings. Some key clinical issues associated with IL-32 include:

Autoimmune Diseases:

• In rheumatoid arthritis (RA), IL-32 expression is elevated in the synovial fluid and tissues, where it contributes to joint inflammation and destruction. IL-32 stimulates the production of matrix metalloproteinases (MMPs), which degrade the extracellular matrix and exacerbate joint damage.

Inflammatory Bowel Disease (IBD):

• Elevated IL-32 levels have been reported in Crohn’s disease and ulcerative colitis, where it promotes intestinal inflammation and dysregulated immune responses. IL-32 may play a role in maintaining chronic inflammation in the gut through the induction of TNF-α and IL-6.

Infectious Diseases:

• IL-32 plays a protective role in infections like tuberculosis, where it enhances macrophage responses to Mycobacterium tuberculosis. It has also been implicated in viral infections, including HIV, where it contributes to the chronic immune activation seen in infected individuals.

Cancer:

• IL-32 can have both pro-tumorigenic and anti-tumorigenic effects, depending on the type of cancer and the surrounding microenvironment. In hepatocellular carcinoma and lung cancer, high levels of IL-32 are associated with increased tumor growth and invasiveness. However, in other cancers such as gastric cancer, IL-32 may contribute to anti-tumor immunity.

Cardiovascular Disease:

• IL-32 has been linked to atherosclerosis, where it may promote the inflammation that drives plaque formation and arterial damage. Its role in promoting endothelial dysfunction and macrophage activation contributes to the progression of atherosclerotic lesions.

Summary

IL-32 is a non-classical cytokine with strong pro-inflammatory properties, playing a significant role in immune regulation, particularly in chronic inflammation, autoimmunity, infection, and cancer. Structurally, IL-32 exists in multiple isoforms, with IL-32γ being the most biologically active. Unlike most cytokines, IL-32 exerts its effects without a specific receptor, instead acting through intracellular signaling pathways. Clinically, IL-32 is implicated in various autoimmune diseases, infectious diseases, and cancers, making it a potential therapeutic target for immune-modulating therapies. Its role in pathogen defense and its association with inflammatory diseases underline its importance as a critical cytokine in immune regulation.