Interleukin-9 (IL-9) is a signaling protein, known as a cytokine, that plays a role in communication between cells in the immune system. Initially identified as a growth factor for T cells and mast cells, IL-9 has since been recognized for its diverse effects on a range of cell types. Understanding IL-9’s functions is important because it is involved in both protective immune responses and the development of certain diseases.
Cellular Origins and Signaling
IL-9 is produced by various immune cells, with T helper 9 (Th9) cells being a major source among CD4+ T lymphocytes. Other cells, including mast cells, natural killer T (NKT) cells, T helper 17 (Th17) cells, regulatory T (Treg) cells, Type 2 Innate Lymphoid Cells (ILC2s), eosinophils, and neutrophils, also contribute to IL-9 production. Naïve T cells can differentiate into IL-9-producing Th9 cells in the presence of specific signals, such as interleukin-4 (IL-4) and transforming growth factor beta (TGFβ).
Once released, IL-9 delivers its messages by binding to a specific protein complex on the surface of target cells, called the IL-9 receptor (IL-9R). This receptor is composed of two subunits: the IL-9Rα chain and the common gamma chain (γc). The binding of IL-9 to its receptor triggers a cascade of events inside the cell, involving the activation of Janus kinases (JAK) and subsequently, Signal Transducers and Activators of Transcription (STAT) proteins. These activated STAT proteins then move to the cell’s nucleus, where they regulate the expression of specific genes, influencing cell survival, proliferation, and the secretion of inflammatory mediators.
Function in Allergic and Inflammatory Responses
IL-9 plays a significant role in allergic and inflammatory conditions, particularly in the airways. It promotes the accumulation and activity of mast cells, which are immune cells that release histamine and other mediators, contributing to immediate allergic reactions. IL-9 acts on both mature mast cells and their progenitors, enhancing their proliferation in the bone marrow and lungs and stimulating their migration to inflamed tissues. This increase in mast cell numbers in the lungs, influenced by IL-9, is linked to the development of airway hyperreactivity, a characteristic feature of asthma.
Beyond mast cell effects, IL-9 directly influences mucus production in the airways. It upregulates the expression of specific mucin genes in airway epithelial cells, leading to increased mucus secretion. Excessive mucus contributes to airway obstruction in conditions like asthma, where IL-9’s presence in lung tissue is associated with the disease’s progression. Elevated levels of IL-9 and IL-9 producing T helper 9 (Th9) cells have been observed in the peripheral blood of individuals with asthma and allergic rhinitis, further linking IL-9 to these allergic responses.
Role in Immunity Against Pathogens
IL-9 also contributes to the body’s defense mechanisms against certain infections, particularly parasitic worms. It plays a part in the type 2 immune response, which is a specialized defense pathway aimed at expelling these invaders. In response to helminth infections, IL-9 production is rapidly induced by both adaptive and innate immune cells.
IL-9 helps the body physically remove parasites from the gut by promoting intestinal contractility and increasing the numbers of mast cells and basophils in affected tissues. This leads to a more efficient expulsion of worms. Studies have shown that IL-9 can be one of the first cytokines expressed during a helminth infection, preceding other type 2 cytokines, and is necessary for their subsequent production and for controlling the parasitic burden.
The Dual Role of IL-9 in Cancer
Interleukin-9 exhibits a complex and sometimes opposing role in cancer development and progression. In some hematological cancers, IL-9 can act as a pro-tumor factor. As a growth factor for lymphocytes, IL-9 may directly stimulate the proliferation of malignant cells and inhibit their natural cell death processes. IL-9 signaling can promote cell survival by activating specific intracellular pathways, thereby contributing to tumor growth.
Conversely, IL-9 can also exert anti-tumor effects, particularly in solid tumors. It can directly inhibit the growth and induce programmed cell death of certain tumor cells. Additionally, IL-9 can enhance the body’s immune response against tumors by boosting the activity of cancer-killing immune cells. This anti-tumor action involves increasing the infiltration of these immune cells into the tumor site and improving their ability to recognize and destroy cancer cells.
Therapeutic Targeting of IL-9
Given IL-9’s involvement in various diseases, particularly allergic conditions, researchers are exploring ways to therapeutically target its activity. One promising approach involves the use of monoclonal antibodies, which are engineered proteins designed to specifically bind to and neutralize IL-9. By blocking IL-9, these antibodies aim to disrupt its signaling pathways and reduce its effects on target cells.
This therapeutic strategy is being investigated primarily for the treatment of severe asthma, where IL-9 contributes to inflammation and airway remodeling. Clinical trials are underway to assess the safety and effectiveness of anti-IL-9 monoclonal antibodies in human patients with asthma. While early results from animal models have shown that blocking IL-9 can alleviate asthma-associated symptoms, further research is ongoing to confirm these benefits and establish IL-9 inhibition as a viable treatment option.