Prostaglandins are required for CREB activation and cellular proliferationduring liver regeneration

The liver responds to multiple types of injury with an extraordinarily well orchestrated and tightly regulated form of regeneration. The response to p artial hepatectomy has been used as a model system to elucidate the molecul ar basis of this regenerative response. In this study, we used cyclooxygena se (COX)-selective antagonists and -null mice to determine the role of pros taglandin signaling in the response of river to partial hepatectomy. The re sults show that liver regeneration is markedly impaired when both COX-1 and COX-2 are inhibited by indocin or by a combination of the COX-1 selective antagonist, SC-560, and the COX-2 selective antagonist, SC-236. Inhibition of COX-2 alone partially inhibits regeneration whereas inhibition of COX-1 alone tends to delay regeneration. Neither the rise in IL-6 nor the activat ion of signal transducer and activator of transcription-3 (STAT3) that is s een during liver regeneration is inhibited by indocin or the selective COX antagonists. In contrast, indocin treatment prevents the activation of CREB by phosphorylation that occurs during hepatic regeneration. These data ind icate that prostaglandin signaling is required during liver regeneration, t hat COX-2 plays a particularly important role but COX-1 is also involved, a nd implicate the activation of CREB rather than STAT3 as the mediator of pr ostaglandin signaling during liver regeneration.