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J. Biol. Chem., Vol. 277, Issue 23, 20431-20437, June 7, 2002
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From the The normal intestinal epithelium is not inflamed
despite contact with a high density of commensal bacteria. Intestinal
epithelial cells (IEC) express low levels of TLR4 and MD-2 and are
lipopolysaccharide (LPS)-unresponsive. We hypothesized that
immune-mediated signals regulate the expression of TLR4 and MD-2 in
IEC. Expression of TLR4 and MD-2 was examined in normal colonic
epithelial cells or intestinal epithelial cell lines. The effect of the
cytokines interferon (IFN)-
TLR4 and MD-2 Expression Is Regulated by Immune-mediated Signals
in Human Intestinal Epithelial Cells*
§,,,,
Inflammatory Bowel Disease Center, Division
of Gastroenterology, Department of Medicine, the Division of
Pediatric Infectious Diseases, Department of Pediatrics, Steven
Spielberg Pediatric Research Center, Burns and Allen Research
Institute, and the ¶ Department of Pathology, Cedars-Sinai Medical
Center, Los Angeles, California 90048
, IFN-
, and tumor necrosis factor-
(TNF-) on TLR4 and MD-2 expression was examined by reverse
transcription-PCR and Western blot. NF-
B transcriptional activation
and interleukin-8 secretion were used as measures of LPS
responsiveness. Native colonic epithelial cells and IEC lines express a
low level of TLR4 and MD-2 mRNA. IFN- regulates MD-2 expression
in both IEC lines, whereas IFN- and TNF- regulate TLR4 mRNA
expression in IEC lines. Pre-incubation with IFN- and/or TNF-
sensitizes IEC to LPS-dependent interleukin-8 secretion. To
examine MD-2 transcriptional regulation, we cloned a 1-kb sequence
proximal to the MD-2 gene translational start site. This promoter
directed expression of a reporter gene in endothelial cells and IEC.
IFN- positively regulated MD-2 promoter activity in IEC.
Co-expression of a STAT inhibitor, SOCS3, blocked IFN--mediated MD-2
promoter activation. T cell-derived cytokines lead to increased
expression of TLR4 and MD-2 and LPS-dependent
pro-inflammatory cytokine secretion in IEC. IFN- regulates
expression of the critical TLR4 co-receptor MD-2 through the Janus
tyrosine kinase-STAT pathway. Th1 cytokines may initiate or perpetuate
intestinal inflammation by altering toll-like receptor
expression and bacterial reactivity.
*
This work was supported by National Institutes of Health
Grants DK02635 (to M. T. A.) and HL66436 and AI40275 (both to
M. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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