TUMOR-NECROSIS-FACTOR-ALPHA DECREASES HEPATOCYTE BILE-SALT UPTAKE ANDMEDIATES ENDOTOXIN-INDUCED CHOLESTASIS

Tumor necrosis factor-alpha (TNF alpha), a cytokine that is produced i n a variety of inflammatory diseases associated with cholestasis, is b elieved to be the primary mediator of the systemic effects of endotoxi n, Thus, we have investigated the role of TNF alpha in the pathogenesi s of endotoxin-induced cholestasis in intact animals, and in the uptak e of taurocholate by cultured hepatocytes, Male Sprague-Dawley rats re ceived either intravenous (Iv) endotoxin (7.5 mg/kg) or monoclonal ant i-TNF alpha antibody followed by endotoxin, Basal bile now and bile sa lt excretion were measured for a 2-hour period, after which all animal s received an Iv bolus of taurocholate (10 mu mol/100 g body weight), Endotoxin decreased basal bile now by 41% and bile salt stimulated bil e now by 38% (n = 12; P <.01), Basal bile salt excretion was decreased 86% after endotoxin administration, Passive immunization with anti-TN F alpha antibody blocked this endotoxin-associated cholestasis. In add ition, rat hepatocytes were isolated and cultured in the presence of e ither endotoxin (10 mu g/mL) or TNF alpha (100 ng/mL) for 24 hours. Th ese primary hepatocyte cultures exhibited a dose- and time-dependent, noncompetitive, inhibition of taurocholate uptake, We postulate that T NF alpha is an important mediator of the cholestasis of sepsis.