ANTIBODY TO TUMOR-NECROSIS-FACTOR ATTENUATES ENDOTOXIN-STIMULATED AMINO-ACID-TRANSPORT IN RAT-LIVER

Background. Endotoxemia stimulates amino acid consumption by the liver , but the regulation of this response is poorly understood. We studied the effect of Escherichia coli endotoxin role of the cytokine tumor n ecrosis factor-alpha (TNF) in regulating this transport activity. Meth ods. We investigated the activities of the Na+-dependent amino acid tr ansport systems A, ASC, and N in hepatic plasma membrane vesicles prep ared from rats treated with endotoxin in vivo. Vesicle purity and func tionality were evaluated by assaying marker enzymes and by the presenc e of classic overshoots. Results. Endotoxin treatment did not alter so dium transport but resulted in time- and dose-dependent 6-fold (system A), 3.5-fold (system N), and 3-fold (system ASC) increases in transpo rt activity secondary to an increase in carrier maximum velocity. Lipo polysaccharide treatment did not alter transporter affinity or plasma membrane sodium transport. Transport activity increased within 2 hours of endotoxin administration, peaked at 4 hours after exposure to lipo polysaccharide, and returned to basal levels within 24 hours. Pretreat ment of animals with an anti-TNF monoclonal antibody diminished the en dotoxin-induced enhancement in transport activity by 50% to 75% by dec reasing carrier maximum velocity. In contrast, when the antibody was g iven after endotoxin challenge, transport activity was not attenuated. Conclusions. The marked acceleration in hepatic amino acid uptake tha t occurs during endotoxemia is secondary to an increased Na+-dependent hepatocyte plasma membrane transport activity and is mediated, in lar ge part by the cytokine TNF.