Regulatory role of the COX-2 pathway in the Nrf2-mediated anti-inflammatory response

Antioxidant responsive element (ARE) mediated gene expression, is a pivotal cellular defense mechanism against the toxicity of electrophiles and reactive oxygen species (ROS). Nrf2 belongs to the Cap-N-Collar family of basic region-leucine zipper transcription factors and has emerged as an essential signal transducer that responds to electrophiles and ROS by regulating transcription via the ARE. The ARE-regulated gene battery consists of detoxification enzymes and antioxidant genes and confers protection against oxidative insults such as hyperoxic lung injury and benzo[a]pyrene-induced tumorigenesis in the forestomach. Recent investigations indicated that the ARE gene battery also plays significant roles in the regulation of inflammation. Indeed, many natural or synthetic substances activating the ARE-mediated transcription pathway inhibit pro-inflammatory gene expression. On the other hand, cyclooxygenase-2 (COX-2) exerts anti-inflammatory roles in the protection against inflammation by certain stimuli. Downstream effectors of the COX-2 pathway include cyclopentenone prostaglandins (cyPGs) such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)). We recently demonstrated that the Nrf2 pathway is activated by endogenous 15d-PGJ(2) during carrageenin-induced inflammation. Thus, cyPGs may act as physiological regulators of Nrf2.