Superinduction of COX‐2 mRNA by cycloheximide and interleukin‐1β involves increased transcription and correlates with increased NF‐κB and JNK activation

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Abstract
Many primary response genes, including cyclooxygenase‐2 (COX‐2), exhibit mRNA superinduction following agonist stimulation in the presence of translational blockers such as cycloheximide. This is widely assumed to result from mRNA stabilisation. However, superinduction of IL‐1β‐induced COX‐2 mRNA levels by cycloheximide in pulmonary type II A549 cells occurred by increased transcription and not by mRNA stabilisation. Furthermore, equivalent effects were observed on NF‐κB binding to COX‐2 promoter κB sites and activation of the Jun N‐terminal kinases (JNK), p54 and p46. These signalling pathways play important roles in COX‐2 induction and may therefore account for the observed increases in COX‐2 transcription. These data are consistent with negative feed‐back involving down‐regulation of NF‐κB by de novo IκBα synthesis and suggest that JNK activation may also be down‐regulated by a cycloheximide sensitive process.