INTERLEUKIN-6 INHIBITS HEPATOCYTE TAUROCHOLATE UPTAKE AND SODIUM-POTASSIUM-ADENOSINE-TRIPHOSPHATASE ACTIVITY

The potential effects of cytokines on hepatocellular transport functio ns remain undefined. Interleukin-g (IL-6) is a cytokine that is produc ed in sepsis, hepatitis, and other inflammatory conditions often assoc iated with cholestasis. Using cultured rat hepatocytes, we have invest igated the effects of IL-6 on hepatocellular bile salt uptake. Because hepatocyte Na+-K+-adenosinetriphosphatase (ATPase) produces the elect rochemical gradient that drives sodium-dependent bile salt cotransport , we also examined the effects of IL-6 on Na+-K+-ATPase activity. Hepa tocytes cultured for 20 h in media containing IL-6 exhibited a dose-de pendent noncompetitive inhibition of [H-3]taurocholate uptake, which w as maximal at an IL-6 dose of: 100 U/ml. IL-6 treatment had no effect on hepatocyte sodium-independent taurocholate uptake. Northern blottin g of RNA from cultured hepatocytes revealed that IL-6 had no effect on steady-state RNA levels of the Na+-taurocholate transporter (Ntcp). H epatocytes incubated with IL-6 for 20 h, however, exhibited a 55% decr ease in hepatocyte Na+-K+-ATPase activity. This effect also was dose d ependent, with maximal inhibition occurring at an IL-6 dose of 100 U/m l. Similar treatment with IL-6 did not influence hepatocyte Mg2+-ATPas e activity. The inhibition of Na+-K+-ATPase activity induced by IL-6 p rovides a putative mechanism for the observed inhibition of sodium-dep endent taurocholate uptake. Since modulation of bile salt transport an d 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 c holestasis of sepsis and other inflammatory disorders.