Abstract
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 α, interleukin (IL) 1β, 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.
Footnotes
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This study was supported by National Institutes of Health Grant ES09649.
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ABBREVIATIONS: LPS, lipopolysaccharide; bDNA, branched DNA signal amplification assay; ELISA, enzyme-linked immunosorbent assay; IL; interleukin; Oatp4, organic anion-transporting polypeptide 4; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor α; Ntcp, Na+/taurocholate-cotransporting polypeptide; Mrp2, multidrug resistance-associated protein 2; Bsep, bile salt export pump; BSP, sulfobromophthalein; TIR, Toll/IL-1 receptor; MyD88/Mal, myeloid differentiation factor 88 (MyD88)-adaptor-like protein; GSH, glutathione.
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↵1 Current address: U.S. Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740.
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↵2 Current address: Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel St., Tucson, AZ 85721.
- Received September 11, 2003.
- Accepted July 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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