IL25 - interleukin 25 |Elisa - Clia - Antibody - Protein

Background

Interleukin 25 (IL-25), also known as IL-17E, is a cytokine that belongs to the IL-17 cytokine family. It is primarily known for its role in the promotion of type 2 immune responses, which are typically associated with allergic inflammation and parasite defense. IL-25 is produced by several cell types, including epithelial cells, T helper type 2 (Th2) cells, eosinophils, mast cells, and macrophages. As a key regulator of Th2 immunity, IL-25 is involved in the induction of cytokines such as IL-4, IL-5, and IL-13, which drive immune responses linked to asthma, allergic rhinitis, and helminth infections.

The role of IL-25 extends beyond its involvement in type 2 immune responses, as it has been implicated in tissue repair, mucosal barrier integrity, and homeostasis. Dysregulation of IL-25 is associated with various inflammatory diseases, including asthma, inflammatory bowel disease (IBD), and atopic dermatitis. In recent years, IL-25 has emerged as a potential therapeutic target for modulating inflammatory and allergic diseases, due to its influence on immune cell recruitment and cytokine production.

Protein Structure

IL-25 is a member of the IL-17 family, which also includes other cytokines such as IL-17A, IL-17B, IL-17C, IL-17D, and IL-17F. This family is characterized by a conserved protein structure, including four anti-parallel β-strands forming a β-sandwich fold, which is a common structural motif among cytokines in the IL-17 family.

Primary Structure:

• IL-25 is encoded by the IL25 gene located on chromosome 14q11.2 in humans.
• The mature IL-25 protein is composed of 177 amino acids and has a molecular weight of approximately 20 kDa. It is synthesized as a precursor protein that undergoes proteolytic processing to generate the mature cytokine.

Secondary and Tertiary Structure:

• IL-25 exhibits a β-sandwich fold, a structure shared by all members of the IL-17 family. This structure is stabilized by cysteine residues, which form intramolecular disulfide bonds that contribute to the protein’s stability and function.
• IL-25 shares around 20-25% sequence identity with other members of the IL-17 family, particularly with IL-17B and IL-17F, which are structurally and functionally similar.

Quaternary Structure and Receptor Binding:

• IL-25 functions by binding to a heterodimeric receptor complex, composed of IL-17 receptor B (IL-17RB) and IL-17 receptor A (IL-17RA). This receptor pairing is distinct from other IL-17 family cytokines, which primarily signal through IL-17RA paired with different co-receptors.
• Upon binding to its receptor complex, IL-25 initiates intracellular signaling cascades, primarily through activation of the NF-κB pathway and MAPK (mitogen-activated protein kinase) pathways, leading to the transcription of various Th2-associated cytokines and inflammatory mediators.

Classification and Subtypes

IL-25 belongs to the broader IL-17 cytokine family, which is classified based on sequence homology, structural similarities, and shared receptor usage. The IL-17 family includes IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F.

• IL-17A and IL-17F are predominantly involved in Th17-driven inflammatory responses, while IL-25 (IL-17E) is unique in its ability to promote Th2-type immune responses.
• Unlike some of the other IL-17 family members that are primarily involved in pro-inflammatory immune responses, IL-25 is specifically associated with anti-parasitic and allergic-type immune reactions, making it a key player in type 2 immunity.

There are no distinct subtypes of IL-25, but it shares functional and structural similarities with IL-17A and IL-17F, particularly in receptor usage and immune modulation.

Function and Biological Significance

IL-25 has emerged as a pivotal cytokine in regulating type 2 immunity. It plays a significant role in immune defense against extracellular pathogens, such as helminths, and in mediating allergic responses. IL-25’s effects are mediated through its action on various immune cells, particularly those involved in type 2 inflammation, such as eosinophils, basophils, Th2 cells, and innate lymphoid cells (ILC2s).

Key Functions:

Induction of Type 2 Immune Responses:

• IL-25 promotes the production of Th2 cytokines, including IL-4, IL-5, and IL-13, which are critical for orchestrating allergic inflammation and immunity against parasites. These cytokines drive the differentiation of Th2 cells and the recruitment of eosinophils and basophils, which are central to the type 2 immune response.
• IL-25 also enhances the production of IgE and promotes goblet cell hyperplasia in the airways, which is important in the defense against helminths and other extracellular pathogens.

Role in Allergic Diseases:

• IL-25 plays a crucial role in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. By enhancing the recruitment of Th2 cells and promoting the secretion of cytokines like IL-4 and IL-13, IL-25 contributes to the chronic inflammation seen in these diseases.
• IL-25 can also activate innate lymphoid cells type 2 (ILC2s), which produce large amounts of Th2 cytokines and are involved in the early phases of allergic inflammation, further amplifying the type 2 immune response.

Barrier Function and Tissue Repair:

• IL-25 is produced by epithelial cells in response to tissue damage or pathogen exposure. It plays a role in maintaining epithelial barrier integrity and promoting tissue repair. In the lung and gastrointestinal tract, IL-25 contributes to the maintenance of mucosal barriers, thus preventing excessive inflammation and damage.
• Through its actions on epithelial cells and its role in regulating goblet cell activity, IL-25 is important for the secretion of mucus and the protection of mucosal surfaces during inflammation.

Immune Cell Recruitment and Activation:

• IL-25 enhances the recruitment of eosinophils, basophils, and macrophages to sites of inflammation. It also activates dendritic cells to skew towards a type 2 phenotype, which further promotes the expansion and activation of Th2 cells.
• This cytokine amplifies the type 2 immune response by activating ILC2s, which serve as early responders in allergic inflammation and are responsible for the production of large quantities of Th2 cytokines even in the absence of T cells.

Regulation of Inflammation:

• Although IL-25 is generally considered to promote inflammation in the context of type 2 immune responses, it can also have anti-inflammatory effects in certain contexts. IL-25 has been shown to suppress Th17 responses, which are associated with autoimmune diseases such as psoriasis and rheumatoid arthritis.
• By inhibiting the production of IL-17A and related cytokines, IL-25 may help to maintain a balance between pro-inflammatory and anti-inflammatory responses.

Clinical Issues

IL-25 is increasingly recognized as a key mediator in inflammatory diseases, particularly those involving allergic inflammation and type 2 immunity. As such, it is considered a potential therapeutic target for allergic diseases and autoimmune conditions.

Diseases and Conditions Associated with IL-25:

Asthma:

• Elevated levels of IL-25 have been observed in the airways of patients with asthma, particularly those with eosinophilic and allergic asthma phenotypes. IL-25 contributes to airway hyperreactivity and mucus production, exacerbating asthma symptoms.
• Targeting IL-25 or its receptors may offer a therapeutic approach for controlling inflammation in severe asthma by dampening Th2-driven immune responses.

Allergic Rhinitis and Atopic Dermatitis:

• IL-25 has been implicated in the pathogenesis of allergic rhinitis and atopic dermatitis. In these conditions, IL-25 promotes the recruitment of immune cells to the skin and mucosa, contributing to chronic inflammation and tissue remodeling.
• Therapeutic strategies aimed at blocking IL-25 could be beneficial in reducing symptoms and preventing the progression of allergic diseases

Inflammatory Bowel Disease (IBD):

• Dysregulated IL-25 signaling has been linked to IBD, including Crohn’s disease and ulcerative colitis. IL-25 can exacerbate inflammation in the gut, and its levels are often elevated in patients with active disease.
• Strategies targeting IL-25 or its signaling pathways may provide a novel approach for managing chronic intestinal inflammation.

Cancer:

• IL-25 has been associated with tumor promotion in certain cancers, particularly those characterized by an inflammatory microenvironment. While it is predominantly linked to enhancing Th2 responses, its role in tumor biology is complex and context-dependent.
• Understanding the dual role of IL-25 in cancer could lead to the development of targeted therapies that either enhance its tumor-suppressive effects or inhibit its pro-tumorigenic properties.

Summary

IL-25 is a critical cytokine involved in regulating type 2 immune responses, particularly in the context of allergic inflammation and parasite defense. Its protein structure, characterized by a β-sandwich fold, enables it to interact with a specific receptor complex that activates various signaling pathways associated with immune regulation. As a key player in promoting the production of Th2 cytokines and enhancing immune cell recruitment, IL-25 is linked to several clinical conditions, including asthma, allergic rhinitis, and inflammatory bowel disease.

Targeting IL-25 or its signaling pathways offers a promising avenue for therapeutic intervention in allergic and autoimmune diseases. Ongoing research continues to elucidate its complex role in health and disease, paving the way for novel strategies aimed at modulating IL-25 activity for therapeutic benefit. Understanding IL-25’s multifaceted roles in immune regulation may ultimately contribute to the development of innovative treatments for conditions characterized by dysregulated immune responses.