SUPERINDUCTION OF COX-2 MESSENGER-RNA BY CYCLOHEXIMIDE AND INTERLEUKIN-1-BETA INVOLVES INCREASED TRANSCRIPTION AND CORRELATES WITH INCREASED NF-KAPPA-B AND JNK ACTIVATION

Many primary response genes, including cyclooxygenase-2 (COX-2), exhib it mRNA superinduction following agonist stimulation in the presence o f translational blockers such as cycloheximide, This is widely assumed to result from mRNA stabilisation, However, superinduction of IL-1 be ta-induced COX-2 mRNA levels by cycloheximide in pulmonary type II A54 9 cells occurred by increased transcription and not by mRNA stabilisat ion, Furthermore, equivalent effects were observed on NF-kappa B bindi ng to COX-2 promoter kappa B sites and activation of the Jun N-termina l kinases (JNK), p54 and p46. These signalling pathways play important roles in COX-2 induction and may therefore account for the observed i ncreases in COX-2 transcription, These data are consistent with negati ve feed-back involving down-regulation of NF-kappa B by de novo I kapp a B alpha synthesis and suggest that JNK activation may also be down-r egulated by a cycloheximide sensitive process. (C) 1997 Federation of European Biochemical Societies.