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

Background information Interleukin (IL)‐1β 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‐1β signalling may help identify therapeutic targets for corneal wound healing; however, mechanisms such as cell migration, a component of IL‐1β‐induced wound healing response in human corneal endothelial cells (CEC), have not been well characterised. Results Stimulation of human CEC with IL‐1β 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 pan–fibroblast 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 κB kinase α/β, leading to FGF2 expression through activation of activator protein 1 (AP‐1) and nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐κB) in human CEC. Treatment of IL‐1β‐stimulated human CEC with either AP‐1 or NF‐κB antagonists decreased FGF2 expression and resulted in reduced IL‐1β‐enhanced cell migration. Co‐treatment of IL‐1β‐stimulated human CEC with both inhibitors completely blocked FGF2 expression and IL‐1β‐enhanced cell migration. Chromatin immunoprecipitation assays demonstrated that AP‐1 and NF‐κB directly bind to the FGF2 promoter following IL‐1β stimulation. Conclusions The results show that binding of IL‐1β to its receptor in human CEC leads to parallel activation of AP‐1 and NF‐κB pathways, leading, in turn, to FGF2 expression and enhanced cell migration.