IL9 - interleukin 9 |Elisa - Clia - Antibody - Protein

Background

Interleukin-9 (IL-9) is a multifunctional cytokine belonging to the type I cytokine family. Originally classified as a T cell growth factor, IL-9 has since been found to influence a variety of immune cells, including T cells, B cells, mast cells, eosinophils, and epithelial cells. Produced predominantly by a subset of CD4+ T cells known as Th9 cells (T helper 9), IL-9 is involved in many immune responses, particularly those related to allergies, asthma, and parasitic infections.

The discovery of IL-9’s wide range of biological activities, from promoting inflammation to supporting tissue repair, has highlighted its dual role as both a protective and pathogenic cytokine. This ambivalence makes IL-9 a key player in immune regulation. While it is essential in protective immunity, especially against helminth infections, its dysregulation is implicated in various allergic diseases and autoimmune disorders, making it a target of therapeutic interest.

Protein Structure

IL-9 is a relatively small glycoprotein with a molecular weight of approximately 14-16 kDa. It consists of 144 amino acids in its mature form and, like other cytokines in the type I cytokine family, it features several conserved structural motifs.

Key structural features of IL-9 include:

• Four α-helix bundle: IL-9 adopts a typical “four α-helix bundle” structure, a characteristic feature of type I cytokines. The helices are arranged in an up-up-down-down fashion, stabilized by hydrophobic interactions.
• Disulfide bonds: IL-9 contains two disulfide bonds, which help stabilize the protein’s tertiary structure, ensuring its proper folding and functional conformation.
• N-terminal region: The N-terminal domain of IL-9 is involved in receptor binding and signal transduction. It contains a few glycosylation sites that contribute to the stability and bioactivity of the protein.
• Receptor interaction: IL-9 mediates its effects by binding to a specific receptor complex composed of the IL-9R (IL-9 receptor α chain) and the γc chain (common gamma chain), which is shared by several cytokine receptors (including IL-2, IL-4, IL-7, IL-15, and IL-21). Upon binding IL-9, this receptor complex activates downstream signaling pathways, primarily the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway. Specifically, STAT3 and STAT5 are the main transcription factors activated by IL-9 signaling, leading to gene expression changes in target cells.

This structural setup allows IL-9 to exert its effects on a variety of immune and non-immune cells.

Classification and Subtypes

IL-9 belongs to the type I cytokine family, which is defined by its reliance on the common gamma chain (γc) for receptor signaling. It is part of a broader network of cytokines that use similar receptor signaling pathways to mediate diverse biological functions, especially in immune regulation.

While IL-9 itself does not have recognized subtypes, its production is tightly regulated by different immune cell types:

• Th9 cells: These specialized CD4+ T cells are the primary source of IL-9. Th9 cells differentiate from naive CD4+ T cells under the influence of specific cytokines, including TGF-β and IL-4.
• Other sources: Though Th9 cells are the main producers of IL-9, other cells such as mast cells, innate lymphoid cells (ILCs), and regulatory T cells (Tregs) can also secrete IL-9 under certain conditions, contributing to both pro-inflammatory and regulatory immune responses.

Function and Biological Significance

IL-9’s biological effects are multifaceted, influencing a wide range of immune and structural cells. Its functions include promoting immune cell activation, differentiation, proliferation, and tissue repair. These functions make IL-9 an important cytokine in both protective immunity and inflammatory diseases.

Primary Functions:

1. Mast Cell Activation and Proliferation: One of IL-9’s most prominent roles is its ability to stimulate mast cell growth, survival, and activation. Mast cells play a crucial role in allergic responses, and IL-9 enhances their ability to produce inflammatory mediators like histamine, proteases, and cytokines. This makes IL-9 a critical cytokine in allergic diseases like asthma and anaphylaxis.
2. Eosinophil Recruitment and Function: IL-9 also affects eosinophils, key players in allergic inflammation and host defense against parasites. By promoting eosinophil survival and function, IL-9 contributes to the pathogenesis of allergic diseases such as asthma and eosinophilic esophagitis.
3. T Cell Growth Factor: Initially characterized as a T cell growth factor, IL-9 promotes the proliferation and survival of activated T cells. This function is particularly important in maintaining Th9 cell populations, which in turn amplify IL-9 production and drive immune responses.
4. Host Defense against Parasites: IL-9 is involved in protective immunity against helminthic infections. It enhances the ability of mast cells and eosinophils to respond to parasitic infections by promoting immune-mediated parasite expulsion. In mouse models, IL-9 has been shown to be essential for the clearance of intestinal parasites like Trichuris muris and Nippostrongylus brasiliensis.
5. Tissue Repair: In addition to its pro-inflammatory functions, IL-9 has been implicated in promoting tissue repair. It stimulates epithelial cell proliferation and enhances mucus production in the lungs and intestines, contributing to the maintenance of mucosal barriers during infection and inflammation.

Clinical Issues

IL-9’s dual role as both a pro-inflammatory cytokine and a tissue repair mediator makes it relevant in a wide range of diseases. Dysregulation of IL-9 production and signaling is associated with several clinical conditions:

1. Asthma and Allergic Diseases: IL-9 is a major player in allergic diseases, particularly asthma. High levels of IL-9 are found in the airways of patients with allergic asthma, where it contributes to airway hyperreactivity, mucus hypersecretion, and eosinophil infiltration. Mast cells activated by IL-9 play a significant role in airway inflammation and bronchoconstriction, leading to asthma symptoms. Similarly, IL-9 has been implicated in other allergic diseases, such as atopic dermatitis and allergic rhinitis.
2. Autoimmune Diseases: In certain autoimmune conditions, IL-9 promotes pathological inflammation. For example, IL-9 has been linked to multiple sclerosis (MS), where it promotes inflammation in the central nervous system (CNS) and contributes to demyelination. Elevated IL-9 levels have also been found in systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), where it plays a role in perpetuating immune dysregulation.
3. Cancer: IL-9’s role in cancer is complex and context-dependent. In some tumors, such as Hodgkin’s lymphoma and acute lymphoblastic leukemia, IL-9 promotes tumor growth and survival by enhancing cell proliferation and inhibiting apoptosis. Conversely, in other settings, IL-9 can have anti-tumor effects by boosting the immune response against tumor cells, particularly through the activation of mast cells and T cells.
4. Helminth Infections: IL-9 is essential for effective immune responses against parasitic helminths. Individuals with deficient IL-9 signaling may have impaired ability to clear these infections, leading to chronic parasitic diseases.
5. Therapeutic Potential: Given its involvement in a wide range of diseases, IL-9 is an attractive target for therapeutic interventions. In asthma and allergic diseases, IL-9 blockade has been explored as a potential treatment strategy to reduce inflammation and airway hyperresponsiveness. Conversely, IL-9 administration is being investigated in cancer immunotherapy and as a means of enhancing host defense in parasitic infections.

Summary

IL-9 is a versatile cytokine that plays critical roles in immune regulation, inflammation, and tissue repair. It is produced primarily by Th9 cells but also by other immune cells like mast cells and eosinophils. Structurally, IL-9 belongs to the type I cytokine family and signals through a receptor complex involving the IL-9R and the common gamma chain, leading to the activation of JAK/STAT pathways.

Biologically, IL-9 promotes mast cell and eosinophil activation, T cell growth, and host defense against parasitic infections. However, its dysregulation is implicated in several diseases, including asthma, autoimmune disorders, and certain cancers. IL-9 has a dual role in both driving inflammation and contributing to tissue repair, making it a key player in both protective immunity and disease pathogenesis.

Understanding IL-9's functions and its role in disease has opened up new therapeutic avenues, with ongoing research focusing on modulating IL-9 signaling to treat allergic diseases, autoimmune conditions, and cancer.