PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1 AND INTERLEUKIN-6 IN THE PERFUSED-RAT-LIVER

The kinetics of the production and release of tumor necrosis factor-al pha (TNF-alpha), interleukin-l (IL-1) and interleukin-6 (IL-6) were in vestigated in the perfused rat liver and in primary cultures of Kupffe r cells after stimulation with lipopolysaccharide (LPS). A small and t ransient accumulation of TNF-alpha could be detected immunohistochemic ally and by cytotoxicity assay in the intracellular space about 1 h af ter addition of LPS to the cultured cells. TNF-alpha release in the pe rfused liver followed similar kinetics as those found in the serum of LPS-treated rats and in primary cultures of rat Kupffer cells. The cyt otoxic TNF-alpha activity of the perfusate attained its maximum (11.5/-2.6 U/ml) 90 min after LPS stimulation and remained nearly constant for further 150 min. 2 mu M dexamethasone reduced the production of TN F-alpha by 10 g of liver during 240 min fi om 46 to 16x10(3) units. Th e production of IL-1 and IL-6 by 10 g of liver during the initial 240 min was 3 and 530x10(3) IU, respectively. The maximal concentrations o f IL-l (1.4+/-0.7 IU/ml) and IL-6 (157+/-60 IU/ml) were found 230 min after LPS addition. The production of IL-l was totally suppressed by 2 mu. dexamethasone. Comparison of the concentrations of TNF-alpha and IL-6 obtained in the perfusate of a LPS-treated liver with those of re combinant cytokines required for the respective effects in vitro revea led that the intrahepatic cytokine production may be sufficient to eli cit important biological effects such as an increased adhesiveness of neutrophils to endothelial cells, the induction of IL-8 and the stimul ation of the synthesis of acute-phase proteins.