Differential effect of cyclooxygenase metabolites on proinflammatory cytokine release by kupffer cells after liver ischemia and reperfusion

background Liver ischemia and reperfusion (l/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 E2 (PGE2) by KC were assessed both in the presence and absence of the cyclo-oxygenase 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 PGE2 release in the I/R group was reduced by 51 % (P<0.05) in comparison with the sham-operated group. Increased release of PGE2 in the later period (32 hours) after I/R was associated with decreased TNF-α release by KC. Inhibition of PGE2 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 PGE2 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.