Interleukin-6 inhibits hepatocyte taurocholate uptake and sodium- potassium-adenosinetriphosphatase activity

The potential effects of cytokines on hepatocellular transport functions remain undefined. Interleukin-6 (IL-6) is a cytokine that is produced in sepsis, hepatitis, and other inflammatory conditions often associated with cholestasis. Using cultured rat hepatocytes, we have investigated the effects of IL-6 on hepatocellular bile salt uptake. Because hepatocyte Na⁺-K⁺- adenosinetriphosphatase (ATPase) produces the electrochemical gradient that drives sodium-dependent bile salt cotransport, we also examined the effects of IL-6 on Na⁺-K⁺-ATPase activity. Hepatocytes cultured for 20 h in media containing IL-6 exhibited a dose-dependent noncompetitive inhibition of [³H]taurocholate uptake, which was maximal at an IL-6 dose of 100 U/ml. IL- 6 treatment had no effect on hepatocyte sodium-independent taurocholate uptake. Northern blotting of RNA from cultured hepatocytes revealed that IL- 6 had no effect on steady-state RNA levels of the Na⁺-taurocholate transporter (Ntcp). Hepatocytes incubated with IL-6 for 20 h, however, exhibited a 55% decrease in hepatocyte Na⁺-K⁺-ATPase activity. This effect also was dose dependent, with maximal inhibition occurring at an IL-6 dose of 100 U/ml. Similar treatment with IL-6 did not influence hepatocyte Mg²⁺- ATPase activity. The inhibition of Na⁺-K⁺-ATPase activity induced by IL-6 provides a putative mechanism for the observed inhibition of sodium-dependent taurocholate uptake. Since modulation of bile salt transport and Na⁺-K⁺- ATPase activity occurred at IL-6 concentrations comparable to the serum levels observed in patients with severe inflammatory states, these findings have potential pathophysiological relevance for the cholestasis of sepsis and other inflammatory disorders.