Interleukin-1β enhances cell migration through AP-1 and NF-κB pathway-dependent FGF2 expression in human corneal endothelial cells

Background information Interleukin (IL)-1 is a major pro-inflammatory cytokine that plays a crucial role in the regulation of inflammation and wound healing in the cornea. Elucidation of IL-1 signalling may help identify therapeutic targets for corneal wound healing; however, mechanisms such as cell migration, a component of IL-1-induced wound healing response in human corneal endothelial cells (CEC), have not been well characterised. Results Stimulation of human CEC with IL-1 activated expression of fibroblast growth factor 2 (FGF2) and resulted in enhanced cell migration. This, in turn, was abolished by treatment with either IL-1 receptor antagonist or SU-5402, a panfibroblast growth factor signalling inhibitor. Phosphatidyl inositol (PI) 3-kinase or IL receptor-associated kinase 1/4 antagonists demonstrated that IL receptor-associated kinase 1/4 activates PI 3-kinase, which in turn phosphorylates p38 and inhibitor B kinase /, leading to FGF2 expression through activation of activator protein 1 (AP-1) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-B) in human CEC. Treatment of IL-1-stimulated human CEC with either AP-1 or NF-B antagonists decreased FGF2 expression and resulted in reduced IL-1-enhanced cell migration. Co-treatment of IL-1-stimulated human CEC with both inhibitors completely blocked FGF2 expression and IL-1-enhanced cell migration. Chromatin immunoprecipitation assays demonstrated that AP-1 and NF-B directly bind to the FGF2 promoter following IL-1 stimulation. Conclusions The results show that binding of IL-1 to its receptor in human CEC leads to parallel activation of AP-1 and NF-B pathways, leading, in turn, to FGF2 expression and enhanced cell migration.