Am. J. Respir. Crit. Care Med., Volume 162, Number 6, December 2000, 2272-2277

Effect of Endogenous and Exogenous Prostaglandin E₂ on Interleukin-1-Induced Cyclooxygenase-2 Expression in Human Airway Smooth-Muscle Cells

ALBINO BONAZZI, MANLIO BOLLA, CAROLA BUCCELLATI, ALICIA HERNANDEZ, SIMONA ZARINI, TERESA VIGANÒ, FRANCESCA FUMAGALLI, SERENA VIAPPIANI, SAULA RAVASI, PIERO ZANNINI, GIUSEPPE CHIESA, GIANCARLO FOLCO, and ANGELO SALA

Center for Cardiopulmonary Pharmacology, University of Milan and Department of Thoracic Surgery, San Raffaele Hospital, Milan, Italy

We studied the effect of endogenous and exogenous prostaglandin E₂ (PGE₂), a metabolite of arachidonic acid through the cyclooxygenase (COX) pathway, on interleukin (IL)-1-induced COX-2 expression, using primary cultures of human bronchial smooth-muscle cells (HBSMC). Treatment with exogenous PGE₂ resulted in enhanced expression of IL-1-induced COX-2 protein and messenger RNA (mRNA) as compared with the effect of the cytokine per se. Inhibition of PGE₂ production with a nonselective COX inhibitor (flurbiprofen, 10 µM) resulted in a significant reduction in IL-1- induced 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 PGE₂ to the transcriptional level of COX-2 mRNA rather than to a potential effect on protein and/or mRNA stabilization. PGE₂ increased adenylate cyclase activity in a concentration dependent manner, and forskolin, a direct activator of adenylate cyclase, caused a marked increase in IL-1-dependent COX-2, suggesting the existence of a causal relationship between the two events. The same results were observed with salbutamol, a bronchodilator that acts by increasing cyclic adenosine monophosphate. The effect of PGE₂ on COX-2 expression may contribute to the hypothesized antiinflammatory role of PGE₂ in human airways, providing a self-amplifying loop leading to increased biosynthesis of PGE₂ during an inflammatory event.

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