Induction of an XXXX -sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs.

@entity10178 @entity16538 @entity3522 @entity117 @entity1443
The transformed monocyte/macrophage cell line J774.2 undergoes apoptosis when treated for 48 h with competitive inhibitors of cyclooxygenase (COX) isoenzymes 1 and 2. Many of these nonsteroid antiinflammatory drugs (NSAIDs), but in particular @entity3522 , induce during this time period a COX activity that coincides with a robust induction of @entity10178 protein. Induction of this activity requires high, apoptosis-inducing concentrations of @entity3522 (>100 microM). Prolonged treatment of J774.2 cells with lower doses of @entity3522 inhibits COX activity, indicating that @entity3522 is a time-dependent, pseudoirreversible inhibitor of @entity10178 . It is difficult to wash out the inhibition. However, the activity evoked by high concentrations of @entity3522 has a profoundly distinct COX active site that allows @entity3522 , its inducer, to be washed readily from its active site. The @entity3522 -induced activity also has the unusual property of being more sensitive to inhibition by @entity1443 (IC50 = 0.1-1.0 mM) than @entity10178 induced with bacterial lipopolysaccharide. Moreover, relative to @entity16538 or @entity10178 , @entity3522 -induced enzyme activity shows significantly reduced sensitivity to inhibition by @entity3522 or other competitively acting nonsteroid antiinflammatory drugs (NSAIDs) and the enzyme activity is insensitive to @entity117 . If the robust induction of @entity10178 observed is responsible for @entity3522 -induced COX enzyme activity, it is clear that @entity10178 can, therefore, exist in two catalytically active states. A luciferase reporter-construct that contains part of the @entity10178 structure and binds into the membrane showed that chronic @entity3522 treatment of fibroblasts results in marked mobilization of the fusion protein. Such a mobilization could result in enzymatically distinct @entity10178 populations in response to chronic @entity3522 treatment.
