Effect of endogenous and exogenous prostaglandin E-2 on interleukin-1 beta-induced cyclooxygenase-2 expression in human airway smooth-muscle cells

We studied the effect of endogenous and exogenous prostaglandin E-2 (PGE(2) ), a metabolite of arachidonic acid through the cyclooxygenase (COX) pathwa y, on interleukin (IL)-1 beta -induced COX-2 expression, using primary cult ures of human bronchial smooth-muscle cells (HBSMC). Treatment with exogeno us PGE(2) resulted in enhanced expression of IL-1 beta -induced COX-2 prote in and messenger RNA (mRNA) as compared with the effect of the cytokine per se. Inhibition of PGE(2) production with a nonselective COX inhibitor (flu rbiprofen, 10 muM) resulted in a significant reduction in IL-1 beta -induce d COX-2 expression, supporting a role of endogenous COX metabolites in the modulation of COX-2 expression. None of the experimental conditions used in the study affected the expression of constitutive cyclooxygenase (COX-1). Treatment with cycloheximide to inhibit translation, and with dexamethasone or actinomycin D to inhibit transcription, linked the effect of PGE(2) to the transcriptional level of COX-2 mRNA rather than to a potential effect o n protein and/or mRNA stabilization. PGE(2) increased adenylate cyclase act ivity in a concentration dependent manner, and forskolin, a direct activato r of adenylate cyclase, caused a marked increase in IL-1 beta -dedependent COX-2 suggesting the existence of a causal relationship between the two eve nts. The same results were observed with salbutamol, a bronchodilator that acts by increasing cyclic adenosine monophosphate. The effect of PGE(2) on COX-2 expression may contribute to the hypothesized antiinflammatory role o f PGE(2) in human airways, providing a self-amplifying loop leading to incr eased biosynthesis of PGE(2) during an inflammatory event.