Interleukin-37 (IL-37) is a protein that facilitates cell signaling, especially within the immune system. As a cytokine, it plays a part in cell-to-cell communication and is recognized as a component in the regulation of inflammation. The scientific community’s understanding of this cytokine is continuously evolving, with ongoing research focused on clarifying its roles in both health and disease.
Discovery and Production of IL-37
Identified in 2000 through computational gene analysis, IL-37 was originally designated as IL-1 family member 7 (IL-1F7). It belongs to the IL-1 family of cytokines, a group of signaling molecules known for their involvement in inflammation. The gene for IL-37 is located on chromosome 2, in proximity to the genes for other IL-1 family members.
The production of IL-37 occurs in a wide range of cells. Key producers include various immune cells such as monocytes, macrophages, dendritic cells, and B cells. Non-immune cells, like the epithelial cells that line body cavities and surfaces, are also capable of generating this cytokine.
The synthesis of IL-37 is often triggered by pro-inflammatory signals, suggesting it functions as a natural feedback mechanism. When the body mounts an inflammatory response, the same signals that promote inflammation can also stimulate the creation of IL-37. This dynamic suggests that IL-37 acts to counterbalance and control the extent of the inflammatory reaction.
IL-37’s Mechanism of Action
IL-37 moderates immune responses through actions both outside and inside the cell. This dual functionality allows it to influence inflammatory processes through distinct pathways. The precursor form of IL-37 can be processed into a mature form by an enzyme called caspase-1, which prepares it for its various roles.
Externally, IL-37 can bind to receptors on the surface of other cells. It interacts with the IL-18 receptor alpha (IL-18Rα) and subsequently recruits another receptor, IL-1 receptor 8 (IL-1R8). This formation of a three-part complex on the cell membrane dampens the cell’s ability to transmit inflammatory signals, thereby reducing the production of inflammatory molecules.
Alternatively, IL-37 can operate from within the cell. After being processed, the mature IL-37 can travel to the cell’s nucleus where it partners with a molecule named Smad3. This complex of IL-37 and Smad3 can then influence gene expression, directly interacting with the cell’s DNA. This suppresses the transcription of genes responsible for producing pro-inflammatory proteins, providing a direct way to control inflammation at its genetic source.
Key Immunomodulatory Functions of IL-37
The primary role of IL-37 in the immune system is to act as a broad suppressor of inflammation. Its presence helps to maintain a balanced immune state, often referred to as homeostasis, by applying a brake to potentially damaging inflammatory responses.
A significant function of IL-37 is its ability to decrease the production of pro-inflammatory cytokines. Research has shown that IL-37 can inhibit the synthesis of molecules like tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6. By limiting these inflammatory agents, IL-37 helps to control the intensity and duration of an inflammatory event.
Beyond suppressing pro-inflammatory signals, IL-37 also modulates the behavior of immune cells. It can inhibit the maturation of dendritic cells, which are responsible for presenting antigens to other immune cells. Furthermore, IL-37 can influence macrophages, encouraging them to adopt an anti-inflammatory M2 phenotype rather than a pro-inflammatory M1 state. This shift contributes to the resolution of inflammation and tissue repair.
The Role of IL-37 in Disease
Altered levels of IL-37 have been linked to a variety of human diseases. In many autoimmune and inflammatory conditions, IL-37 appears to have a protective function by limiting the immune system’s attack on the body’s own tissues. Its presence is often associated with reduced disease severity.
In autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and psoriasis, studies have observed dysregulated IL-37 expression. In these conditions, the immune system mistakenly targets healthy cells, and IL-37 can help to mitigate this response. In inflammatory conditions like inflammatory bowel disease (IBD) and atherosclerosis, IL-37 has been shown to exert protective effects.
The role of IL-37 extends to infectious diseases, where it can modulate the immune response to pathogens, preventing an overly aggressive inflammatory reaction. In the context of cancer, the function of IL-37 is more complex. It can sometimes be protective by reducing inflammation that might fuel tumor growth, but in other scenarios, it could hinder the anti-tumor immune response.
Therapeutic Research on IL-37
The anti-inflammatory properties of IL-37 have made it a subject of therapeutic research. Scientists are exploring the possibility of using recombinant IL-37, a lab-made version of the protein, to treat diseases characterized by excessive inflammation. This approach aims to supplement the body’s natural levels of this cytokine to better control inflammatory and autoimmune disorders.
Preclinical studies involving animal models have shown encouraging results. For instance, administering recombinant IL-37 to mice has been shown to protect against conditions like colitis, myocardial infarction, and experimental arthritis. These studies provide a basis for the potential of IL-37 as a therapeutic agent in various disease models.
Despite promising preclinical data, challenges remain in developing IL-37-based therapies for human use. Issues such as ensuring protein stability, developing effective delivery methods, and understanding potential side effects require further investigation. More extensive clinical trials in humans are necessary to confirm its safety and efficacy for treating a range of inflammatory conditions.