Interleukin-3 (IL-3) is a signaling molecule, a cytokine, that facilitates cell communication throughout the body. Cytokines help regulate the body’s responses to various stimuli, including inflammation and infection. IL-3 is involved in the immune system and the process of producing blood cells. Understanding its mechanisms provides insights into how the body maintains health and responds to disease.
The Molecular Blueprint of IL-3
Interleukin-3 is a protein encoded by the IL3 gene, located on chromosome 5 at band 5q31.1 in humans. The IL3 gene directs the production of the IL-3 protein. The mature human IL-3 protein consists of 133 amino acids and has a molecular weight of approximately 17 kDa.
IL-3 is typically produced as a monomer. This protein is primarily synthesized by activated T cells, which are a type of white blood cell, but also by monocytes, macrophages, and stromal cells. The three-dimensional structure of IL-3 is important for its function, allowing it to interact with its receptors on other cells. Its structure includes two noncontiguous helical domains, which are involved in binding to its receptor.
Orchestrating Blood Cell Development
IL-3 plays a significant role in hematopoiesis, the continuous process of blood cell formation that occurs primarily in the bone marrow. It acts as a growth factor, promoting the survival, proliferation, and differentiation of hematopoietic stem and progenitor cells into mature blood cell types. This includes the development of white blood cells such as granulocytes, monocytes, and dendritic cells.
Beyond white blood cells, IL-3 also supports the formation of red blood cells (erythroid cells) and platelets (megakaryocytes). IL-3 achieves these effects by binding to its specific receptor, the Interleukin-3 Receptor (IL-3R), found on the surface of target cells. The IL-3R is a heterodimeric complex composed of two subunits: a specific alpha subunit (IL-3Rα) that binds IL-3, and a common beta subunit (βc) that is shared with receptors for IL-5 and GM-CSF.
The binding of IL-3 to IL-3Rα induces the association of IL-3Rα with the βc subunit, forming a high-affinity receptor complex. This association triggers a cascade of intracellular signaling events, including the activation of Janus kinase 2 (JAK2). This signaling pathway, along with the activation of the Ras and PI3K pathways, promotes cell cycle progression, DNA synthesis, and inhibits programmed cell death, thereby supporting the proliferation and differentiation of blood cells.
IL-3’s Dual Role in Disease
Interleukin-3 exhibits complex roles in various disease states, acting as both a beneficial and detrimental factor. Its involvement spans autoimmune conditions, infectious diseases, and different forms of cancer. This dual nature highlights the delicate balance of immune regulation within the body.
In autoimmune conditions, dysregulation of IL-3 can contribute to inflammation. For instance, in experimental autoimmune myocarditis, IL-3 amplifies cardiac inflammation by increasing monocyte accumulation, which intensifies the inflammatory response. In certain models of inflammatory arthritis, however, IL-3 inhibits TNFα-induced bone resorption and prevents cartilage and bone loss in joints.
Regarding infectious diseases, IL-3 plays a role in the immune response to pathogens. During viral infections, such as SARS-CoV-2, IL-3 levels have been identified as a predictive marker for clinical outcome and disease severity. In a mouse model of HSV-1 infection, IL-3 protected against viral pneumonia by promoting the recruitment of plasmacytoid dendritic cells into the lung. These dendritic cells are important for initiating innate antiviral immunity and enhancing T cell priming.
In the context of cancer, IL-3 can sometimes promote tumor growth, while in other situations, it may be targeted for therapy. For example, in acute myeloid leukemia (AML), IL-3 has been shown to support the growth and survival of leukemic cells. This observation has led to the development of IL-3 inhibitors, which aim to reduce the proliferation of cancer cells by blocking IL-3 signaling. Conversely, therapies utilizing a recombinant toxin combined with human IL-3 have shown promise in treating leukemias. These examples underscore that IL-3’s impact varies significantly with the specific disease and the cellular environment.