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J Biol Chem, Vol. 275, Issue 13, 9222-9229, March 31, 2000
Tumor Necrosis Factor- and Interleukin-1 Inhibit
Apolipoprotein B Secretion in CaCo-2 Cells via the Epidermal Growth
Factor Receptor Signaling Pathway*
Shubha
Murthy ,
Satya N.
Mathur, and
F. Jeffrey
Field
From the Department of Internal Medicine and Veterans Affairs,
University of Iowa, Iowa City, Iowa 52242
In inflammatory conditions of the gut, cytokines
are released into the mucosa and submucosa propagating and sustaining
the inflammatory response. In CaCo-2 cells, we have shown that various inflammatory cytokines interfere with the secretion of lipids, an
effect that is likely caused by the release of a ligand to the
epidermal growth factor (EGF) receptor. In the present study, the role
of the EGF receptor signaling pathway and the effects of the cytokines
tumor necrosis factor- (TNF- ) and and interleukin 1 (IL-1 )
on triacylglycerol-rich lipoprotein secretion were investigated. CaCo-2
cells were incubated with oleic acid to enhance triacylglycerol-rich
lipoprotein secretion. TNF- and IL-1 significantly decreased the
basolateral secretion of apolipoprotein B (apoB) mass, with IL-1
being more potent. Tyrphostin, an inhibitor of the EGF receptor
intrinsic tryosine kinase, prevented or markedly attenuated the
decrease in apoB secretion by TNF- or IL-1 . Both cytokines
increased the phosphorylation of the EGF receptor by 30 min. Moreover,
phosphotyrosine immunoblots of the EGF receptor demonstrated an
increase in tyrosine residues phosphorylated by 0.5 and 6.5 h. At
both these time points, TNF- and IL-1 also decreased the binding
of EGF to its cell surface receptor. At 6.5 h, activation of the
EGF receptor was sustained. In contrast, the early activation of the
receptor was only transient as receptor phosphorylation and binding of
EGF to its receptor returned to basal levels by 2 h. Preventing
ligand binding to the EGF receptor by a receptor-blocking antibody
attenuated receptor activation observed after 6.5 h. This did not
occur at 0.5 h, suggesting that early activation of the EGF
receptor was non-ligand-mediated. Similarly, apoB secretion was
inhibited by an early non-ligand-mediated process; whereas at the later
time, inhibition of apoB secretion was ligand-mediated. Thus, the
inflammatory cytokines TNF- and IL-1 interfere with the secretion
of triacylglycerol-rich lipoproteins by both early and delayed
signaling events mediated by the EGF receptor signaling pathway.
*
This work was supported by the Veterans Affairs and National
Institutes of Health Grants HL49264 and 56032.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.
To whom correspondence should be addressed: Dept. of Internal
Medicine and Veterans Affairs, University of Iowa, 200 Hawkins Dr.,
Iowa City, IA 52242. Tel.: 319-335-7073; Fax: 319-356-7893; E-mail:
shubha-murthy@uiowa.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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