Differential regulation of hepatic organic cation transporter 1, organic anion-transporting polypeptide 1a4, bile-salt export pump, and multidrug resistance-associated protein 2 transporter expression in lymphocyte-deficient mice associates with interleukin-6 production.
Cholestasis results from interrupted bile flow and is associated with immune-mediated liver diseases. It is unclear how inflammation contributes to cholestasis. The aim of this study was to determine whether T and B cells contribute to hepatic transporter expression under basal and inflammatory conditions. C57BL/6J wild-type mice or strains lacking T, B, or both T and B cells were exposed to lipopolysaccharide (LPS) or saline, and livers were collected 16 hours later. Branched DNA signal amplification was used to assess mRNA levels of organic anion-transporting polypeptides (Oatp) 1a1, 1a4, and 1b2; organic cation transporter (Oct) 1; canalicular bile-salt export pump (Bsep); multidrug resistance-associated proteins (Mrp) 2 and 3; and sodium-taurocholate cotransporting polypeptide (Ntcp). Real-time polymerase chain reaction analysis was used to correlate changes of transporter expression with interleukin-1b (IL-1b), IL-6, IL-17A, IL-17F, tumor necrosis factor-α (TNF-α), and interferon-γ expression in the liver. LPS treatment inhibited Bsep and Oct1 mRNA expression, and this was abrogated with a loss of T cells, but not B cells. In addition, the absence of T cells increased Mrp2 mRNA expression, whereas B cell deficiency attenuated Oatp1a4 mRNA in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deficiency. Lymphocyte deficiency altered basal and inflammatory IL-6, but not TNF-α or IL-1b, mRNA expression. Taken together, these data implicate lymphocytes as regulators of basal and inflammatory hepatic transporter expression and suggest that IL-6 signaling may play a critical role.
Center for Cellular and Molecular Immunology, Department of Surgery (C.E.B., C.M.T., R.M.M., S.C.M.) and Department of Microbiology and Immunology (S.C.M.), University of Missouri School of Medicine, Columbia, Missouri; and Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (A.L.D., A.D.L., N.J.C.).
Connor E
CE
Bodeman
Anika L
AL
Dzierlenga
Catherine M
CM
Tally
Ryan M
RM
Mulligan
April D
AD
Lake
Nathan J
NJ
Cherrington
Susan C
SC
McKarns
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000502:physiology; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000502:physiology; D050811:Octamer Transcription Factor-1 / Q000096:biosynthesis* / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis* / Q000502:physiology
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D015850:Interleukin-6; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; C490549:Abcb11 protein, mouse; C464433:Oatp2 protein, mouse; C494166:Pou2f1 protein, mouse; C577686:interleukin-6, mouse