Cyclooxygenase‐1 and ‐2 enzymes differentially regulate the brain upstream NF‐κB pathway and downstream enzymes involved in prostaglandin biosynthesis (original) (raw)

2006, Journal of Neurochemistry

We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E 2 (PGE 2 ), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX-1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX-2 and phospholipase A 2 enzymes (cPLA 2 and sPLA 2 ), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES-1, and ) 2) in wild type and COX-1 -/mice. We found that brain PGE 2 concentration was significantly increased, whereas thromboxane B2 (TXB 2 ) concentration was decreased in COX-1 -/mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-jB pathway, and also an increase in the upstream cPLA 2 and sPLA 2 enzymes. The mechanism of NF-jB activation in the COX-1 -/mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-jB, as well as the increased protein levels of phosphorylated IjBa and of phosphorylated IKKa/b. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE 2 production being metabolically coupled with COX-2 and TXB 2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca 2+ -dependent PLA 2 , and terminal mPGES-2, to overcome defects in brain AA cascade.