Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis

Figure 1

This figure shows relevant cell types, mediators, and potential pharmacological targets associated with IL-23 and IL-17 pathways (IL-23/IL-17 Axis), which are operative within the context of inflammatory bowel disease (IBD). Bacterial ligands (lipopolysaccharide [LPS] and peptidoglycan [PGN]) bind to their respective toll-like receptors (TLR4 and TLR2) and induce IL-23 release from antigen-presenting cells (APC’s). IL-23 binds to the IL-23 receptor (IL-23R) to stimulate expansion of Th-17-producing cells, which release IL-17. In addition, interactions between TL1A (tumor necrosis factor-like molecule) on APC’s and DR3 (death receptor 3) on T lymphocytes induces the secretion of IL-17. These pathways also promote the secretion other proinflammatory cytokines like IL-6 and TNF-α. IL-17 stimulates the expression of adhesion molecules (e.g., ICAM-1) on endothelial cells, as well as the release of IL-6 and IL-8 from myofibroblasts and epithelial cells. IL-8 acts as a chemotactic factor for neutrophil influx into the intestine. Infiltrating neutrophils release inflammatory mediators like matrix metalloproteinases (MMP’s) and inducible nitric oxide synthase (iNOS). This sequelae of pathogenic events leads to the chronic inflammation and epithelial cell damage associated with IBD.