Inhibition of cytoplasmic phospholipase A 2 expression by glucocorticoids in rat intestinal epithelial cells

Abstract

Background & Aims: Glucocorticoids are the most potent and widely accepted anti-inflammatory agents in the treatment of pathological conditions of the gastrointestinal tract in part by inhibiting the synthesis of proinflammatory prostanoids and leukotrienes. Multiple forms of phospholipase A 2 may be associated with the production of these metabolites; this study focused on the molecular mechanism(s) by which glucocorticoids control expression of the arachidonyl-selective, cytosolic phospholipase A 2 (cPLA 2) in intestinal cells. Methods: Northern analysis, a transcriptional assay, and enzymatic evaluation were used to access expression of the cPLA 2 gene in rat small intestinal epithelial and mouse fibroblast cell lines treated with dexamethasone. Results: Basal cPLA 2 messenger RNA (mRNA) expression was repressed 75% in the presence of dexamethasone with a concomitant decrease in enzymatic activity. Nuclear runoff assays showed a marked decline in de novo cPLA 2 RNA synthesis, implicating a transcriptional mechanism associated with the dexamethasone-mediated suppression of cPLA 2. Induced expression of cPLA 2 mRNA by several proinflammatory cytokines was blocked by cotreatment with dexamethasone. Conclusions: Glucocorticoids are capable of markedly altering basal and cytokine-stimulated cPLA 2 gene expression in intestinal epithelial cells, leading to a reduction in arachidonate pools in these cells. Dexamethasone-dependent inhibition occurs through a direct reduction of de novo cPLA 2 gene transcription. GASTROENTEROLOGY 1999;116:855-864