background: Liver ischemia and reperfusion (I/R) induce Kupffer cell (KC) activation with increased release of proinflammatory cytokines. Prostaglandins are potent counterregulatory mediators to control the production of cytokines by macrophages.methods: To study the role of cyclooxygenase metabolites for the release of proinflammatory cytokines by KC in liver I/R, Sprague-Dawley rats were subjected to 20-minute global hepatic ischemia and 60 minutes of reperfusion. Sham-operated animals were used as controls. Kinetics of spontaneous and lipopolysaccharide (LPS)-induced release of proinflammatory cytokines and prostaglandin E 2 (PGE 2 ) by KC were assessed both in the presence and absence of the cyclooxygenase inhibitor ibuprofen.results: Early after liver I/R (4, 16 hours) the spontaneous secretion of TNF-α (+1,058%), IL-1α (+152%), and IL-6 (+161%) by KC was increased (P <0.05), while PGE 2 release in the I/R group was reduced by 51% (P <0.05) in comparison with the sham-operated group. Increased release of PGE 2 in the later period (32 hours) after I/R was associated with decreased TNF-α release by KC. Inhibition of PGE 2 production by ibuprofen induced a prolonged and enhanced production of TNF-α, while the release of IL-1α and IL-6 was not affected.conclusions: Liver I/R leads to a temporary suppression of PGE 2 release by KC, while the release of TNF-α is increased. Thus, during early reperfusion, excessive secretion of TNF-α by KC may be the result of the absent negative feedback control of cyclooxygenase metabolites.