Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease

Figure 4 Schematic representation of chitinase 3-like 1-associated β-catenin activation signaling pathway, which is inhibited by methylxanthine derivatives. Binding of extracellular chitinase 3-like 1 (CHI3L1) to a putative receptor on plasma membrane activates the intracellular phosphatidylinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which leads to β-catenin activation by translocating this protein from cytoplasm into nucleus. Methylxanthine derivatives, including caffeine, pentoxifylline and theophylline, directly down-regulate CHI3L1 mRNA expression and inhibit CHI3L1 protein functions, leading to reduced CHI3L1-associated AKT activation and prevent down-stream β-catenin nuclear translocation with different degrees of efficacy.