Interleukin-6 regulates hepatic transporters during acute-phase response.
Cholestasis develops during inflammatory conditions characterized by the release of cytokines like interleukin-6 (IL-6), which is the major player in the hepatic acute-phase response. However, the exact contribution of IL-6 to transporter down-regulation is unclear. Therefore, we compared wild-type and IL-6-deficient mice after IL-6-injection and induction of an aseptic (turpentine-injection) or septic (LPS-injection) acute-phase response. Down-regulation of basolateral (Ntcp, Oatp1, and Mrp3) and canalicular (Mrp2, Bsep) transporter mRNA occurred after treatment with IL-6, turpentine, and LPS. In IL-6-deficient mice, turpentine failed to decrease mRNA-levels of basolateral and canalicular transporters, whereas LPS-mediated down-regulation of Ntcp, Mrp3, and Mrp2 was abolished at later time points (24 h). In conclusion, induction of an aseptic and septic acute-phase response leads to the down-regulation of basolateral and canalicular organic anion transporters. IL-6 is required for transporter down-regulation during aseptic inflammation. Furthermore, IL-6 also contributes to transporter regulation during LPS-induced cholestasis at more delayed time points.
Department of Internal Medicine III, Aachen University (RWTH), Aachen, Germany.
Elmar
E
Siewert
Christoph G
CG
Dietrich
Frank
F
Lammert
Peter C
PC
Heinrich
Siegfried
S
Matern
Carsten
C
Gartung
Andreas
A
Geier
D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D015850:Interleukin-6 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D008070:Lipopolysaccharides; D008099:Liver / Q000276:immunology* / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014425:Turpentine
D015850:Interleukin-6; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D014425:Turpentine