Up-regulation of cyclooxygenase-1 in neuroblastoma cell lines by retinoic acid and corticosteroids

Cyclooxygenases-1 and -2 are both expressed in neuronal cells in vivo. In t he neuroblastoma cell lines NG108 and N2a, however, only cyclooxygenase-l w as detectable. Differentiation of the cells with retinoic acid increased cy clooxygenase-l mRNA and protein expression within 24 and 48 h, respectively . A further increase was observed when the cells were concomitantly treated with the glucocorticoid dexamethasone (a 2-3-fold increase compared with r etinoic acid alone). In the absence of retinoic acid, dexamethasone only sl ightly up-regulated cyclooxygenase-l expression. The inhibitor of protein s ynthesis cycloheximide abrogated the effect of dexamethasone, indicating th e involvement of newly synthesised proteins. Retinoic acid increased the tr anscription of cyclooxygenase-l mRNA, determined with a luciferase-coupled promoter construct. Dexamethasone only slightly augmented cyclooxygenase-l- promoter activity but increased cyclooxygenase-l mRNA stability. Other cort icosteroids, hydrocortisone and aldosterone, also up-regulated cyclooxygena se-l whereas neurosteroids or oestrogen were ineffective. Up-regulation was mediated primarily by the glucocorticoid receptor, because the receptor an tagonist RU486 strongly reduced the effects of all corticosteroids. This in dicated that in NG108 cells, the mineralocorticoid aldosterone may bind to the glucocorticoid receptor. Treatment of NG108 or N2a cells with corticost eroids did not alter the morphological phenotype obtained during differenti ation. We thus show that corticosteroids, which down-regulate cyclooxygenas e expression in most cell types, up-regulate cyclooxygenase-l during neuron al differentiation.