Transient FGF stimulation of various cell types results in FGF memory – a sustained blockage of efficient proliferative response to FGF and other growth factors. FGF memory establishment requires HDAC activity, indicating its epigenetic character. FGF treatment stimulates proinflammatory NFκB signaling, which is also critical for FGF memory formation. The search for FGF-induced mediators of FGF memory revealed that FGF stimulates HDAC-dependent expression of the inflammatory cytokine IL1α. Similarly to FGF, transient cell treatment with recombinant IL1α inhibits the proliferative response to further FGF and EGF stimulation, but does not prevent FGF receptor-mediated signaling. Interestingly, like cells pretreated with FGF1, cells pretreated with IL1α exhibit enhanced restructuring of actin cytoskeleton and increased migration in response to FGF stimulation. IRAP, a specific inhibitor of IL1 receptor, and a neutralizing anti-IL1α antibody prevent the formation of FGF memory and rescue an efficient proliferative response to FGF restimulation. A similar effect results following treatment with the anti-inflammatory agents aspirin and dexamethasone. Thus, FGF memory is mediated by proinflammatory IL1 signaling. It may play a role in the limitation of proliferative response to tissue damage and prevention of wound-induced hyperplasia.
FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2-5 day quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of “FGF memory” during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFκB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of “FGF memory” may be based on epigenetic changes. We suggest that “FGF memory” can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. “FGF memory” may present a natural obstacle to the efficient application of recombinant FGFs for the treament of ulcers, ischemias and wounds.
We found that transient FGF stimulation of various cell types results in the novel phenomenon termed “FGF memory” – a sustained blockage of efficient proliferative response to FGF, PDGF or EGF. FGF memory establishment requires HDAC activity, indicating its epigenetic character. FGF treatment stimulates the proinflammatory NFkappaB signaling, which is also critical for FGF memory formation. The search of potential FGF‐induced mediators of FGF memory revealed that FGF induces a sustained expression of the inflammatory cytokine IL1alpha, and this induction is abolished by HDAC inhibitors. Similarly to FGF pretreatment, transient cell treatment with recombinant IL1alphainhibits the proliferative response to further FGF stimulation. However, cells pretreated with FGF or IL1alpha exhibit an enhanced restructuring of actin cytoskeleton and migration in response to FGF. IL1alpha‐prestimulated cells respond to FGF treatment by ERK1/2 phosphorylation and expression of cyclin D1, but not of cyclin A. Both IRAP, a specific inhibitor of IL1 receptor, and neutralizing anti‐IL1alphaantibodies prevent the formation of FGF memory and rescue an efficient proliferative response to FGF restimulation. Thus, FGF memory is mediated by the endogenous IL1alpha. It may play a role in the limitation of proliferative response to tissue damage and prevention of wound‐induced hyperplasia.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.