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 contransport, 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 Mg(2+)-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.
Green
R M
RM
Division of Gastroenterology, Brockton/West Roxbury Veterans Affairs Medical Center, Boston, Massachusetts.
Whiting
J F
JF
Rosenbluth
A B
AB
Beier
D
D
Gollan
J L
JL
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D015850:Interleukin-6 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013656:Taurocholic Acid / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013656:Taurocholic Acid; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase