Interleukin-37 Upregulation Protects Against Inflammatory Bowel Disease and Colitis-Associated Cancer
Background
Inflammatory bowel disease (IBD) is a chronic, idiopathic inflammatory disorder of the intestine that significantly increases the risk of colorectal cancer (CRC), specifically colitis-associated cancer (CAC). The precise etiology and pathogenesis of IBD remain poorly understood, and current treatments often fail to achieve sustained remission or prevent cancer progression. Interleukin (IL)-37, a member of the IL-1 family, has emerged as a key player due to its potent anti-inflammatory properties across various inflammatory diseases and cancers. Understanding its role could reveal novel therapeutic avenues for these challenging conditions.
Study Design
This comprehensive review synthesizes recent advances regarding the expression, biological functions, and molecular mechanisms of IL-37 in the context of IBD and CAC. Researchers systematically analyzed accumulating evidence from preclinical and clinical studies to elucidate how IL-37 mediates its anti-inflammatory effects. The review also explores the therapeutic potential of modulating IL-37 activity, aiming to provide novel insights into its underlying mechanisms and future clinical applications for intestinal inflammatory and cancerous conditions.
Results
The review highlights that IL-37 expression is consistently upregulated in both IBD and CAC, where it exerts significant protective roles. Mechanistically, IL-37 mediates its anti-inflammatory effects through two primary pathways. One involves its translocation into the nucleus, forming a complex with small mother against decapentaplegic homolog 3 (SMAD3), which modulates gene expression. The second mechanism involves IL-37 binding to extracellular interleukin-18 receptor (IL-18R) and IL-1 receptor-related receptor 8 (IL-1R8), with IL-1R8 being abundantly expressed in the gastrointestinal tract. This binding initiates signaling cascades that suppress inflammatory responses. >Accumulating evidence strongly demonstrates that IL-37 acts as a crucial endogenous brake on inflammation, mitigating disease progression in both IBD and CAC models and patient cohorts.
Key Findings
- IL-37 expression is consistently upregulated in both Inflammatory Bowel Disease (IBD) and Colitis-Associated Cancer (CAC).
- IL-37 exerts protective anti-inflammatory effects in IBD and CAC, mitigating disease progression.
- IL-37 mediates anti-inflammatory actions by translocating into the nucleus in complex with
SMAD3. - IL-37 also binds to extracellular
IL-18RandIL-1R8, suppressing inflammatory signaling. - The
IL-1R8receptor, crucial for IL-37's action, is abundantly expressed in the gastrointestinal tract.
Why It Matters
Understanding IL-37's protective roles and mechanisms offers a compelling new target for therapeutic intervention in IBD and CAC. Modulating IL-37 activity could lead to novel anti-inflammatory and anti-cancer strategies, potentially improving patient outcomes where current immunosuppressive agents fall short or carry significant side effects. This research moves beyond symptomatic treatment, suggesting approaches that could directly address the underlying inflammatory drivers of disease and cancer progression. While still in the preclinical and review stage, this knowledge lays the groundwork for developing future peptide-based or gene therapy protocols to enhance endogenous IL-37 levels or activity.
il-37
inflammatory-bowel-disease
colitis-associated-cancer
anti-inflammatory
cytokine
il-1-family