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Infection and Immunity, July 2002, p. 3433-3442, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3433-3442.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Role of Toll-Like Receptors in Changes in Gene Expression and NF-{kappa}B Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

Shubing Liu,* David J. Gallo, Angela M. Green, Debra L. Williams, Xiaoyan Gong, Richard A. Shapiro, Andrea A. Gambotto, Elisabeth L. Humphris, Yoram Vodovotz, and Timothy R. Billiar

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Received 6 September 2001/ Returned for modification 12 October 2001/ Accepted 2 April 2002

The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive to lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) by which LPS stimulates cultured hepatocytes remain uncertain. Cultures of primary mouse hepatocytes were incubated with LPS to assess its effects on the global gene expression, hepatic transcription factors, and mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that LPS modulates the selective expression of more than 80 genes and expressed sequence tags. We have shown previously that hepatocytes express CD14, which is required both for uptake and responsiveness to LPS. In other cells, responsiveness to microbial products requires expression of Toll-like receptors (TLR) and their associated accessory molecules. Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules. The MAP kinase extracellular signal-regulated kinase 1/2 was phosphorylated in response to LPS in mouse hepatocytes, and the levels of phosphorylation were lower in hepatocytes from TLR4-null mice. NF-{kappa}B activation was reduced in TLR4-mutant or -null hepatocytes compared to control hepatocytes, and this defect was partially restored by adenoviral transduction of mouse TLR4. Thus, hepatocytes respond to nanogram concentrations of LPS through a TLR4 response pathway.

* Corresponding author. Mailing address: Department of Surgery, University of Pittsburgh, Montefiore University Hospital, 3459 Fifth Ave., Pittsburgh, PA 15213. Phone: (412) 647-5288. Fax: (412) 647-5959. E-mail: shubing{at}pitt.edu.

Editor: R. N. Moore

Infection and Immunity, July 2002, p. 3433-3442, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3433-3442.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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