Vol. 303, Issue 3, 1001-1006, December 2002

Origins of Prostaglandin E₂: Involvements of Cyclooxygenase (COX)-1 and COX-2 in Human and Rat Systems

Francesco Giuliano and Timothy D. Warner

Department of Cardiac, Vascular, and Inflammation Research, The William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom

Prostaglandin (PG) E₂ is a major cyclooxygenase (COX) product at inflammatory sites where it contributes to local increases in blood flow, edema formation, and pain sensitization. Using rats in vivo and rat and human blood in vitro, we have examined the roles of COX-1 and COX-2 in the production of PGE₂. In anesthetized rats treated with bacterial lipopolysaccharide (LPS) to induce the expression of COX-2, the marked increase in PGE₂ production that followed bolus intravenous injection of arachidonic acid (3 mg kg¹) was strongly inhibited by diclofenac but largely unaffected by the COX-2-selective inhibitor DFP (5,5- dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone). In rat blood in vitro, aspirin strongly inhibited the production of PGE₂ that followed either acute exposure to calcium ionophore, A23187 (calcimycin) (50 µM, 15 min), or incubation with LPS for 18 h. In contrast, human whole blood only produced significant levels of PGE₂ when incubated with LPS. Rat leukocytes expressed COX-2 and produced PGE₂ when exposed to LPS but not when acutely stimulated with A23187. Rat platelets, but not human platelets, also produced significant amounts of PGE₂ when acutely stimulated with A23187. These data show that when exposed to an inflammatory stimulus, rat whole blood produces increased levels of PGE₂ through induction of COX-2 in blood leukocytes. Rat blood, unlike human blood, may also produce copious amounts of PGE₂ via the actions of COX-1 enzyme constitutively present in platelets. These data may well explain why in rats COX-2-selective inhibitors have been reported not to produce the full anti-inflammatory effects associated with standard nonsteroid anti-inflammatory drugs.