Interleukin-10: The Master Regulator of Immune Homeostasis
Immunology / Cytokines
Structure and Cellular Sources
- Interleukin-10 (IL-10) is a cytokine with potent anti-inflammatory properties, composed of 178 amino acids in the form of a homodimer.
- Identified in 1989 as cytokine synthesis inhibitory factor (CSIF).
- Secreted by several immune cells: T regulatory cells (Tregs), T helper 2 cells, macrophages, dendritic cells, and B cells.
- Contains six α-helices folded in a compact V-shaped structure required for receptor interaction and biological activity.
- Structural framework well preserved during evolution, highlighting its significance in immune regulation.
Signalling Mechanisms and Regulation
- IL-10 activates its receptor, a complex system including IL-10R1 (alpha chain) and IL-10R2 (beta chain).
- Binding to its receptor leads to activation of the JAK-STAT signalling pathway, with STAT3 as the major effector, along with some STAT1 and STAT5.
- Results in the expression of genes responsible for inhibiting inflammatory processes.
- Production regulated at transcriptional, post-transcriptional, and epigenetic levels.
- Modulated by cytokines, pathogens, and environmental cues to allow optimal immune responses while avoiding excessive inflammation.
Immunoregulatory Functions
- IL-10 regulates the immune response through multiple pathways:
- Inhibits synthesis of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-12) in macrophages and dendritic cells.
- Decreases costimulatory molecule and MHC class II on antigen-presenting cells (APCs).
- Enhances B cell survival, proliferation, and antibody secretion, especially IgA important for mucosal immunity.
- Supports development and function of regulatory T cells while suppressing effector T cell responses.
- Essential for preventing excessive immune responses and maintaining tissue homeostasis.
Role in Disease and Pathology
- Lack of IL-10 signalling linked to inflammatory bowel diseases, particularly early-onset colitis.
- In autoimmune diseases, affected IL-10 signalling leads to enhanced inflammation and tissue damage.
- Some pathogens and tumors exploit IL-10 to escape immune responses, promoting persistent infection or immune evasion.
- Elevated IL-10 in chronic infections can suppress protective immune responses.
- Cancer cells upregulate IL-10 production, creating an immunosuppressive environment that promotes tumor growth and metastasis.
Therapeutic Applications and Future Perspectives
- Recombinant IL-10 tested for inflammatory disorders (e.g., inflammatory bowel disease, rheumatoid arthritis), but systemic administration has shown mixed results.
- Focus on developing more precise delivery methods, including cell-specific carriers and modified IL-10 with enhanced therapeutic characteristics.
- In cancer immunotherapy, strategies aimed at suppressing IL-10 signalling to boost anti-tumor immune responses.
- IL-10-producing regulatory B cells being investigated as potential cellular therapies for autoimmune diseases.
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