The body’s immune system operates through a complex communication network, using proteins called cytokines as messengers between cells. A specific family of these, interleukins, facilitates communication primarily between white blood cells. Among them, Interleukin-4 (IL-4) and Interleukin-13 (IL-13) are two closely related molecules central to a particular kind of immune activity known as a Type 2 immune response.
They are encoded by adjacent genes and share about 25% of their protein sequence, hinting at their structural and functional relationship. While involved in normal bodily processes, their signaling is most associated with the development of allergies and certain inflammatory conditions.
The Shared Signaling Pathway
The overlapping effects of Interleukin-4 and Interleukin-13 stem from the cellular machinery they use to transmit signals. Immune cells are covered in receptors, proteins that act like locks waiting for a molecular key to initiate a response. Both IL-4 and IL-13 can interact with a receptor component called the IL-4 receptor alpha chain (IL-4Rα), a common point of entry for their signals.
Two main receptor configurations are involved. The Type I receptor is composed of the IL-4Rα chain and the common gamma chain. This complex is exclusive to IL-4, giving it unique capabilities, such as influencing the development of certain T cells, that IL-13 does not possess.
The second configuration, the Type II receptor, is where the overlap occurs. This receptor is formed when the IL-4Rα chain pairs with the IL-13 receptor alpha 1 chain (IL-13Rα1). Both IL-4 and IL-13 can activate this Type II complex; IL-13 initiates the signal by first binding to IL-13Rα1, which then recruits the shared IL-4Rα chain.
Because many cell types, including non-immune cells like those lining the airways and skin, predominantly express the Type II receptor, they respond to both cytokines. The presence and ratio of these receptor types on a cell’s surface dictate whether the subsequent immune reaction is driven by IL-4, IL-13, or both.
Role in Allergic and Inflammatory Responses
The signaling of IL-4 and IL-13 is a primary driver of Type 2 inflammation, the process underlying most allergic diseases. When the body is exposed to a harmless substance like pollen, these cytokines orchestrate an exaggerated immune reaction, causing the symptoms of asthma, atopic dermatitis (eczema), and allergic rhinitis.
One of their main functions is to instruct B-cells to switch production to a specific antibody known as Immunoglobulin E (IgE). In a non-allergic person, IgE levels are very low, but in allergic individuals, IL-4 and IL-13 drive high levels of IgE. These antibodies then attach to the surface of mast cells and basophils, priming them for a reaction.
This priming sets the stage for the classic allergic response. When the allergen is encountered again, it binds to the IgE on these mast cells, causing them to release a flood of inflammatory chemicals like histamine, leading to immediate symptoms like sneezing and itching. IL-4 and IL-13 also recruit other inflammatory cells, especially eosinophils, to the site of exposure. This prolongs the inflammatory response and contributes to the chronic tissue damage seen in many allergic conditions.
Beyond directing immune cells, IL-4 and IL-13 also affect structural cells. In the airways of individuals with asthma, these cytokines stimulate epithelial cells to produce excess mucus and contribute to airway hyperresponsiveness, making the airways twitchy and prone to narrowing. In the skin of those with atopic dermatitis, they disrupt the epidermal barrier by decreasing the production of proteins that hold skin cells together, allowing allergens to penetrate more easily.
Functions in Normal Immunity and Tissue Repair
Although known for their role in allergies, IL-4 and IL-13 perform necessary functions for health. Their roles evolved as part of Type 2 immunity, a defense mechanism geared toward expelling parasitic worms, or helminths. During a helminth infection, these cytokines coordinate events to physically remove the parasites. They stimulate smooth muscle contractility and increase mucus production in the gut, which helps to trap and expel the worms. This anti-parasite defense is considered the original, beneficial purpose of the Type 2 immune pathway.
Beyond fighting infections, IL-4 and IL-13 are involved in tissue repair and wound healing. After an injury, an initial inflammatory phase clears debris, and these cytokines help dampen that phase to prevent excessive damage, promoting a shift toward a tissue-reconstructive state. They influence macrophages to adopt a pro-repair phenotype that supports healing.
These cytokines also influence the remodeling of the extracellular matrix, the structural scaffold that supports cells in tissues, by promoting the synthesis of collagen. While this is beneficial for healing, dysregulation can lead to fibrosis, or excessive scarring, in chronic inflammatory conditions.
Therapeutic Targeting of IL-4 and IL-13
The involvement of IL-4 and IL-13 in Type 2 inflammation has made their signaling pathway a target for drug development. Advances in biotechnology have led to biologic drugs, specifically a class of medications called monoclonal antibodies. These are laboratory-engineered proteins designed to bind to a single target, like a cytokine or receptor, blocking its function with high precision.
This targeted approach differs from traditional immunosuppressants, which often dampen the entire immune system and can have broad side effects. By focusing on the specific molecules driving a disease, biologics can interrupt the inflammatory cascade more selectively. For diseases driven by IL-4 and IL-13, monoclonal antibodies can physically block their shared receptor component, IL-4Rα.
A prominent example is Dupilumab, a monoclonal antibody designed to bind directly to the IL-4Rα subunit. By occupying this part of the receptor complex, Dupilumab prevents both IL-4 and IL-13 from binding and activating either the Type I or Type II receptor. This dual blockade shuts down the downstream signaling pathways that lead to IgE production and eosinophil recruitment, addressing multiple aspects of the allergic response at once.
Dupilumab has received approval for treating several Type 2 inflammatory conditions, including moderate-to-severe atopic dermatitis, certain types of severe asthma, and chronic rhinosinusitis with nasal polyposis.