Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling

We recently determined that transient FGF stimulation results in a stable inhibition of proliferative response to repeated FGF treatment (Poole et al., 2014). This phenomenon termed “FGF memory” has been detected in fibroblasts, endothelial cells, mesenchymal stem cells, and adipose-derived stem cells. Cell stress occurring in damaged tissues can results in the nonclassical release of FGF1 (Prudovsky et al., 2008). We hypothesized that FGF memory may serve to moderate the proliferative response after tissue damage, and thus prevent hyperplasia and decrease scar formation. Establishment of FGF memory depends on NFkB signaling and requires histone deacetylase (HDAC) activity (Poole et al., 2014). Based on these results, a study was undertaken to understand the molecular mechanisms underlying FGF memory. We found that FGF enhances the expression of interleukin (IL) 1alpha, and this effect depends on HDAC activity. Similarly to FGF, transient treatment with IL1alpha drastically inhibits the proliferative response to subsequent stimulation with FGF but does not interfere with FGF-promoted signaling and cell migration. Moreover, cell pretreatment with both FGF1 and IL1alpha blocks the proliferative response to an unrelated growth factor, EGF. FGF memory is abolished by IRAP, the competitive inhibitor of IL1 receptor type I, and a specific neutralizing antibody against IL1alpha. In addition, anti-inflammatory agents aspirin and dexamethasone eliminate it. Collectively, these results show that FGF memory is mediated by IL1alpha production resulting in enhanced inflammatory signaling.