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Prostaglandin E 2 and microsomal prostaglandin E synthase‐2 expression are decreased in the cyclooxygenase‐2‐deficient mouse brain despite compensatory induction of cyclooxygenase‐1 and Ca 2+ ‐dependent phospholipase A 2
Author(s) -
Bosetti Francesca,
Langenbach Robert,
Weerasinghe Gayani R.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02829.x
Subject(s) - cyclooxygenase , prostaglandin , prostaglandin e2 , cytosol , phospholipase a2 , medicine , endocrinology , enzyme , isozyme , prostaglandin e , arachidonic acid , intracellular , microsome , prostaglandin h2 , chemistry , prostaglandin d2 , biology , biochemistry
We previously demonstrated that brain cyclooxygenase (COX)‐2 mRNA and protein levels, and prostaglandin E 2 (PGE 2 ) level, are down‐regulated in cytosolic phospholipase A 2 (cPLA 2 ) ‐deficient mice. To further investigate the interaction between upstream and downstream enzymes involved in brain prostaglandin synthesis, we examined expression and activity of COX‐1, of different PLA 2 enzymes and of prostaglandin E synthase (PGES) enzymes in COX‐2 –/– mice. We found that the PGE 2 level was decreased by 51.5% in the COX‐2 –/– mice brains, indicating a significant role of COX‐2 in brain formation of PGE 2 . However, when we supplied exogenous arachidonic acid (AA) to brain homogenates, COX activity was increased in the COX‐2 –/– mice, suggesting a compensatory activation of COX‐1 and an intracellular compartmentalization of the COX isozymes. Consistent with COX‐1 increased activity, brain expression of COX‐1 protein and mRNA also was increased. Activity and expression of cPLA 2 and secretory PLA 2 (sPLA 2 ) enzymes, supplying AA to COX, were significantly increased. Also, the PGE 2 biosynthetic pathway downstream from COX‐2 was affected in the COX‐2 –/– mice, as decreased expression of microsomal prostaglandin E synthase‐2 (mPGES‐2), but not mPGES‐1 or cytosolic PGES, was observed. Overall, the data suggest that compensatory mechanisms exist in COX‐2 –/– mice and that mPGES‐2 is functionally coupled with COX‐2.