Kupffer cell tumor necrosis factor-alpha production is suppressed during liver regeneration.
Mammalian liver regeneration following resection invokes intrinsic hepatic responses which result in rapid tissue repair. The role of soluble immune cytokines in this phenomenon is not known. The capacity of Kupffer cells (KC) from regenerating liver to produce the potent cytokine TNF-alpha was evaluated. Twenty-four hours after 70% partial hepatectomy (PHx) or sham operation, Kupffer cells were harvested from collagenase-digested Wistar-Furth rat livers and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 microM), 5 x 10(5) KC were repleted with fresh media with or without 2.5 micrograms/ml lipopolysaccharide (LPS). Supernatant TNF-alpha activities (units/ml) were measured using the L929 fibroblast lysis assay. With LPS, sham KC TNF-alpha levels were significantly higher (P less than 0.001) than those for PHx KC. Indomethacin significantly increased PHx KC TNF-alpha levels, but did not affect those for sham KC, suggesting autoregulation by arachidonic acid cyclooxygenase metabolites following PHx. We conclude that KC TNF-alpha production is suppressed following PHx by a mechanism apparently regulated by eicosanoid metabolism. During the stress of hepatic regeneration, a coordinated limitation of excessive TNF-alpha responses by PHx liver KC may naturally protect the host.
Callery
M P
MP
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.
Kamei
T
T
Flye
M W
MW
D000818:Animals; D016861:Cyclooxygenase Inhibitors; D005260:Female; D006498:Hepatectomy / Q000379:methods; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D007728:Kupffer Cells / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D051381:Rats; D011920:Rats, Inbred WF; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D016861:Cyclooxygenase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin