Differential effect of cyclooxygenase metabolites on proinflammatory cytokine release by Kupffer cells after liver ischemia and reperfusion.
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 E2 (PGE2) 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-alpha (+1,058%), IL-1alpha (+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-alpha release by KC. Inhibition of PGE2 production by ibuprofen induced a prolonged and enhanced production of TNF-alpha, while the release of IL-1alpha 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-alpha is increased. Thus, during early reperfusion, excessive secretion of TNF-alpha by KC may be the result of the absent negative feedback control of cyclooxygenase metabolites.
Wanner
G A
GA
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Müller
P
P
Ertel
W
W
Busch
C J
CJ
Menger
M D
MD
Messmer
K
K
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000098:blood supply*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone