Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-κB pathway and downstream enzymes involved in prostaglandin biosynthesis

Authors

  • Sang-Ho Choi,

    1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Robert Langenbach,

    1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
    Search for more papers by this author
  • Francesca Bosetti

    1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author

Address correspondence and reprint requests to Francesca Bosetti, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: frances@mail.nih.gov

Abstract

We have recently reported that cyclooxygenase (COX)-2-deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E2 (PGE2), 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 A2 enzymes (cPLA2 and sPLA2), 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 PGE2 concentration was significantly increased, whereas thromboxane B2 (TXB2) concentration was decreased in COX-1–/– mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-κB pathway, and also an increase in the upstream cPLA2 and sPLA2 enzymes. The mechanism of NF-κB activation in the COX-1–/– mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-κB, as well as the increased protein levels of phosphorylated IκBα and of phosphorylated IKKα/β. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE2 production being metabolically coupled with COX-2 and TXB2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca2+-dependent PLA2, and terminal mPGES-2, to overcome defects in brain AA cascade.

Ancillary