Skip Navigation



ToxSci Advance Access published online on October 13, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi003
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
83/1/197    most recent
kfi003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Li, N.
Right arrow Articles by Klaassen, C. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, N.
Right arrow Articles by Klaassen, C. D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received December 21, 2003
Accepted August 28, 2004

Systems Toxicology

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

Ning Li 1 and Curtis D. Klaassen 1*

1 Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160

* To whom correspondence should be addressed. E-mail: cklaasse{at}kumc.edu.


  Abstract

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-1{beta} (IL-1{beta}), 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-1{beta}, 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-1{beta} , or IL-6 individually or in combination did not suppress activity of mouse Oatp4 promoter (-4.8kb/+30). Therefore, LPS-induced down-regulation of Oatp4 appears to be independent of TNF-{alpha}, IL-1{beta}, IL-6 or iNOS.

Keywords: Oatp4; LPS; TNF; IL-1; IL-6; iNOS.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.