The immune system uses a complex network of signaling molecules, known as cytokines, to coordinate its responses against pathogens and maintain bodily balance. These proteins facilitate communication between various immune cells and direct their activities. Cytokines influence cell growth, differentiation, and overall immune function, ensuring a regulated and effective defense mechanism. Understanding these signals is fundamental to comprehending how the body manages health and disease.
Understanding IL-35
Interleukin-35 (IL-35) is a unique cytokine in the IL-12 family, known for its role in immune suppression. It is composed of two protein subunits: p35 (IL-12α) and Epstein-Barr virus-induced 3 (EBI3). These subunits combine to form a heterodimeric protein.
While IL-35 was initially identified as being produced by activated regulatory T cells (Tregs), its cellular sources have expanded. Other immune cells that secrete IL-35 include:
Regulatory B cells (Bregs)
CD8+Foxp3+ Tregs
Tolerogenic dendritic cells
Macrophages
Vascular endothelial cells
Smooth muscle cells
Monocytes
The expression of its p35 and EBI3 subunits can be influenced by pro-inflammatory stimuli like TNF-α and IFN-γ.
How IL-35 Regulates Immunity
IL-35 primarily functions as an immune-suppressive cytokine, playing a significant role in limiting inflammatory responses. It exerts its effects by binding to specific receptors on target cells, which initiates downstream signaling pathways, notably involving the activation of STAT1 and STAT4 proteins in T cells. In B cells, IL-35 signaling can lead to the phosphorylation of STAT1 and STAT3.
IL-35 inhibits the proliferation and function of effector T cells, such as Th1 and Th17 cells, by limiting their early cell division. This suppression helps to dampen excessive inflammatory reactions. IL-35 also promotes the development and function of other regulatory immune cells, including IL-35-producing induced regulatory T cells (iTr35) and IL-10-producing regulatory B cells (IL-10+Bregs), fostering a positive feedback loop for immune tolerance.
IL-35’s Impact on Disease
IL-35 impacts various health conditions, particularly autoimmune diseases where its immunosuppressive capabilities are beneficial. Lower concentrations of IL-35 are observed in patients with active systemic lupus erythematosus (SLE), inversely correlating with disease severity. IL-35 also shows a protective role in experimental models of inflammatory bowel disease (IBD), with lower serum levels found in human IBD patients. In conditions like rheumatoid arthritis (RA) and multiple sclerosis (MS), IL-35’s ability to curb inflammation suggests potential for mitigating disease progression.
The role of IL-35 in cancer is intricate and sometimes contradictory. In some contexts, IL-35 produced by macrophages within the tumor microenvironment can suppress anti-tumor immunity, potentially promoting tumor growth and metastasis. Elevated circulating IL-35 levels have been identified in various human cancers, including acute myeloid leukemia, pancreatic ductal adenocarcinoma, and colorectal cancer, suggesting it might contribute to tumor progression. Conversely, research also explores how IL-35 might be leveraged for anti-tumor effects.
Exploring IL-35 as a Therapy
The immune-modulating properties of IL-35 make it a promising candidate for therapeutic interventions, particularly in autoimmune and chronic inflammatory conditions. Administering recombinant IL-35 has shown beneficial effects in preventing colitis in mouse models of inflammatory bowel disease. Its capacity to suppress effector T cell proliferation and induce regulatory immune cells positions it as a target for restoring immune balance in diseases driven by overactive immune responses.
Developing IL-35-based therapies involves strategies like direct administration of the cytokine or targeting its specific pathways. The aim is to harness its immunosuppressive effects to reduce inflammation and promote immune tolerance without causing widespread immune suppression, a challenge with conventional treatments. Research focuses on overcoming challenges such as stability, targeted delivery, and precise dosage for optimal therapeutic outcomes in human conditions.