Interleukin-10 (IL-10) is a signaling molecule that cells use to communicate, playing a role in maintaining the body’s internal balance. This communication occurs through complex signaling pathways. IL-10 modulates immune responses and helps maintain equilibrium within the immune system.
The Role of IL-10 in the Immune System
IL-10 primarily functions as an anti-inflammatory cytokine. It limits excessive immune responses, preventing damage to the body’s own tissues from an overactive immune system. This cytokine helps the immune system tolerate harmless substances, a process known as immune tolerance. IL-10 can suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-12, typically released by immune cells during an inflammatory response.
IL-10 is produced by various immune cells, including monocytes, macrophages, dendritic cells (DCs), B cells, and T cell subsets like Th1, Th2, Th17, and regulatory T (Treg) cells. It targets diverse cells, leading to broad anti-inflammatory activity. Macrophages, for example, express higher levels of the IL-10 receptor, making them a primary target for IL-10’s inhibitory effects. This widespread production and responsiveness allow IL-10 to act as a natural “brake” on the immune system, preventing overly aggressive responses to pathogens or other stimuli.
How IL-10 Signaling Works
IL-10 initiates its effects by binding to the IL-10 receptor (IL-10R) on target cells. This receptor is composed of two IL-10 receptor 1 (IL-10R1) subunits and two IL-10 receptor 2 (IL-10R2) subunits, forming a tetrameric complex. The IL-10R1 subunit primarily binds IL-10 with high affinity and is expressed mainly on hematopoietic cells, including T cells, B cells, natural killer (NK) cells, mast cells, and dendritic cells. The IL-10R2 subunit, on the other hand, is expressed more widely across various cell types and acts as an accessory signaling component.
Upon IL-10 binding to IL-10R1, the receptor complex activates intracellular enzymes called Janus kinases (JAKs), specifically JAK1 and Tyk2. These activated JAKs phosphorylate tyrosine residues on the intracellular domain of IL-10R1. These sites serve as docking points for Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 is then phosphorylated by JAK1 and Tyk2, forming homodimers that move into the cell’s nucleus. There, they bind to specific DNA sequences, influencing gene expression and suppressing inflammatory responses.
IL-10 Signaling and Disease
Dysregulation of IL-10 signaling contributes to various disease states. When IL-10 levels or its activity are too low, the immune system can become overactive, leading to excessive inflammation and autoimmune conditions. Deficiencies in IL-10 or its receptor are linked to early-onset inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis. In these conditions, insufficient IL-10 signaling can result in an uncontrolled immune response to the gut microbiota, leading to tissue damage. Reduced IL-10 production by certain immune cells, such as regulatory B cells, has also been correlated with disease flares in systemic lupus erythematosus (SLE), highlighting its protective role in preventing autoimmune activity.
Conversely, abnormally high levels of IL-10 or overactive IL-10 signaling can suppress the immune system too much, potentially hindering its ability to effectively clear infections or fight cancer. In some cancers, tumor cells themselves produce IL-10, or the tumor microenvironment can induce IL-10 production by immune cells, creating an immunosuppressive environment that allows the tumor to evade immune surveillance and grow. For example, certain melanomas and lung adenocarcinomas exhibit enhanced IL-10 expression, which can be associated with a poorer prognosis. Similarly, in chronic infections, elevated IL-10 can attenuate the activity of immune cells like macrophages, contributing to persistent infections.
Therapeutic Approaches Targeting IL-10 Signaling
IL-10 signaling pathways are targets for therapeutic intervention in various diseases. Strategies to enhance IL-10 activity are being explored for conditions involving excessive inflammation or autoimmunity. One approach involves administering recombinant IL-10, which is a laboratory-produced version of the cytokine. While early trials with recombinant human IL-10 showed some clinical and endoscopic improvement in conditions like mild to moderately active Crohn’s disease, its direct use has been limited by factors such as a short half-life in the body and potential off-target effects. To address these challenges, researchers are developing modified versions of IL-10, such as PEGylated IL-10, where polyethylene glycol (PEG) chains are attached to prolong its presence in the bloodstream and improve its efficacy.
Another innovative strategy is gene therapy, which involves delivering genetic material into a patient’s cells to induce the sustained production of IL-10 at sites of inflammation. Non-viral gene therapy platforms are being developed to express modified variants of IL-10, aiming to provide longer-lasting relief for chronic inflammatory conditions such as osteoarthritis and neuropathic pain. Conversely, in certain cancers where IL-10 promotes tumor growth, therapeutic approaches aim to inhibit IL-10 activity. This can involve using monoclonal antibodies that neutralize IL-10 or block its receptor, thereby diminishing its ability to suppress anti-tumor immune responses and potentially enhancing the effectiveness of other cancer treatments like checkpoint inhibitors.