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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/G285    most recent 00425.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by McElroy, S. J. Articles by Polk, D. B. PubMed PubMed Citation Articles by McElroy, S. J. Articles by Polk, D. B.

INFLAMMATION/IMMUNITY/MEDIATORS

Tumor necrosis factor inhibits ligand-stimulated EGF receptor activation through a TNF receptor 1-dependent mechanism

Departments of ¹Pediatrics and ²Cell Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 20 September 2007 ; accepted in final form 3 May 2008

Tumor necrosis factor (TNF) and epidermal growth factor (EGF) are key regulators in the intricate balance maintaining intestinal homeostasis. Previous work from our laboratory shows that TNF attenuates ligand-driven EGF receptor (EGFR) phosphorylation in intestinal epithelial cells. To identify the mechanisms underlying this effect, we examined EGFR phosphorylation in cells lacking individual TNF receptors. TNF attenuated EGF-stimulated EGFR phosphorylation in wild-type and TNFR2^–/–, but not TNFR1^–/–, mouse colon epithelial (MCE) cells. Reexpression of wild-type TNFR1 in TNFR1^–/– MCE cells rescued TNF-induced EGFR inhibition, but expression of TNFR1 deletion mutant constructs lacking the death domain (DD) of TNFR1 did not, implicating this domain in EGFR downregulation. Blockade of p38 MAPK, but not MEK, activation of ERK rescued EGF-stimulated phosphorylation in the presence of TNF, consistent with the ability of TNFR1 to stimulate p38 phosphorylation. TNF promoted p38-dependent EGFR internalization in MCE cells, suggesting that desensitization is achieved by reducing receptor accessible to ligand. Taken together, these data indicate that TNF activates TNFR1 by DD- and p38-dependent mechanisms to promote EGFR internalization, with potential impact on EGF-induced proliferation and migration key processes that promote healing in inflammatory intestinal diseases.

intestinal inflammation; epithelial cells; growth factors; cytokines; p38