Interleukin Networks in Ulcerative Colitis: Pathogenic Mechanisms, Context-Dependent Functions, and Therapeutic Opportunities

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease characterized by dysregulated mucosal immunity, epithelial barrier dysfunction, and persistent intestinal inflammation. Interleukins are central mediators of communication between epithelial cells, innate immune cells, and adaptive lymphocytes and therefore have a critical influence on the initiation, progression, and resolution of intestinal inflammation. However, their effects in UC are highly heterogeneous and may vary according to the cellular source, disease stage, tissue compartment, and local inflammatory environment. This review summarizes current evidence regarding the roles of key interleukins in UC pathogenesis and therapeutic development. Pro-inflammatory cytokines, including IL-1β, IL-6, IL-12, IL-23, and IL-13, contribute to inflammatory amplification through inflammasome activation, JAK/STAT and NF-κB signaling, Th1/Th17-cell responses, leukocyte recruitment, and disruption of epithelial barrier function. In contrast, IL-10 and IL-37 generally exert immunoregulatory effects by limiting inflammatory signaling, supporting regulatory T-cell and macrophage functions, and promoting mucosal homeostasis. Other interleukins, including IL-17, IL-18, IL-22, IL-33, and IL-36, exhibit context-dependent activities that may either aggravate inflammation or contribute to epithelial repair and tissue protection. Notably, therapeutic targeting of the IL-12/23 axis has demonstrated substantial clinical efficacy, whereas interventions directed against other interleukin pathways remain investigational or have produced variable results. The clinical development of interleukin-targeted therapies is further influenced by disease heterogeneity, pathway redundancy, treatment timing, and safety considerations. A better understanding of interleukin networks and their interactions with the intestinal barrier, microbiota, and immune-cell populations may facilitate the identification of predictive biomarkers and the development of more precise, stage-specific therapeutic strategies for UC.