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0090-9556/04/3211-1265-1271$20.00
DMD 32:1265-1271, 2004

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DOWN-REGULATION OF MOUSE ORGANIC ANION-TRANSPORTING POLYPEPTIDE 4 (Oatp4; Oatp1b2; Slc21a10) mRNA BY LIPOPOLYSACCHARIDE THROUGH THE TOLL-LIKE RECEPTOR 4 (TLR4)

Ning Li, Supratim Choudhuri1, Nathan J. Cherrington2, and Curtis D. Klaassen

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas

Lipopolysaccharide (LPS) causes a systemic reaction known as sepsis, which is frequently associated with cholestasis. Many biological effects produced by LPS are thought to be mediated by Toll-like receptor 4 (TLR4). Organic anion-transporting polypeptide 4 (Oatp4; Slc21a10) mediates hepatic uptake of bile acids and other organic anions. The purpose of this study was to determine 1) whether LPS decreases Oatp4 mRNA levels; 2) the role of TLR4 in the LPS-induced down-regulation of Oatp4; and 3) the time course of serum concentrations of tumor necrosis factor {alpha}, interleukin (IL) 1ß, and IL-6 after LPS administration. For the dose-response study, LPS (1 mg/kg i.p.) produced a significant decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice, and higher doses produced slightly greater decreases. However, none of the doses of LPS examined significantly decreased Oatp4 mRNA levels in TLR4-mutant C3H/HeJ mice. For the time-response study, LPS (5 mg/kg i.p.) produced a rapid decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice. The maximal decrease in Oatp4 mRNA levels (80%) was observed 12 h after LPS administration and returned to control levels thereafter. In contrast, LPS did not produce a significant decrease in Oatp4 mRNA levels at any time in TLR4-mutant C3H/HeJ mice. These findings demonstrate that LPS decreases Oatp4 mRNA levels in mice, and the decrease is mediated through TLR4.

Address correspondence to: Dr. Curtis D. Klaassen, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail: cklaasse{at}kumc.edu




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