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ToxSci Advance Access originally published online on October 13, 2004
Toxicological Sciences 2005 83(1):197-203; doi:10.1093/toxsci/kfi003
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Toxicological Sciences vol. 83 no. 1 © Society of Toxicology 2005; all rights reserved.

Lipopolysaccharide-Induced Down-Regulation of Organic Anion Transporting Polypeptide 4 (Oatp4; Slc21a10) Is Independent of Tumor Necrosis Factor-{alpha}, Interleukin-1ß, Interleukin-6, or Inducible Nitric Oxide Synthase

Ning Li and Curtis D. Klaassen1

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160

Received December 21, 2003; accepted August 28, 2004

Organic anion transporting polypeptide 4 (Oatp4; Slc21a10) is expressed almost exclusively in liver, where it mediates uptake of a variety of compounds, including bile acids, as well as other endo- and xenobiotics, across hepatic sinusoidal membranes in a Na+-independent manner. Lipopolysaccharide (LPS) has been shown to decrease Oatp4 mRNA levels in a dose- and time-dependent manner in Toll-like receptor 4 (TLR4)-normal (C3H/OuJ) mice, but not in TLR4-mutant (C3H/HeJ) mice. Moreover, after LPS administration, serum concentrations of tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) are markedly lower in TLR4-mutant mice than in TLR4-normal mice. Thus, TLR4 is considered an upstream mediator of LPS-induced decrease in mouse Oatp4 mRNA. LPS is thought to alter liver gene expression through LPS-induced cytokines or nitric oxide (NO). TNF receptor p55 (TNFRp55) and type I IL-1 receptor (IL-1RI) mediate the biological functions of TNF-{alpha} and IL-1ß, respectively. Therefore, to determine whether endogenous cytokines or NO are mediators of LPS-induced down-regulation of Oatp4, Oatp4 mRNA levels were determined in mice deficient in the TNFRp55, IL-1RI, IL-6, or inducible nitric oxide synthase (iNOS) after LPS administration. Mice homozygous for a targeted deletion of genes for TNFRp55, IL-1RI, IL-6, or iNOS exhibited similar decreases in Oatp4 mRNA levels as wild-type mice after LPS administration. Moreover, in mouse hepatoma cells, treatment with TNF-{alpha}, IL-1ß, or IL-6 individually or in combination did not suppress activity of mouse Oatp4 promoter (–4.8 kb to +30). Therefore, LPS-induced down-regulation of Oatp4 appears to be independent of TNF-{alpha}, IL-1ß, IL-6, or iNOS.

Key Words: Oatp4; LPS; TNF; IL-1; IL-6; iNOS.


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