Open AccessTNF-α induces upregulation of EGFR expression and signaling in human colonic myofibroblasts
Author(s) -
James J. Yoo,
Citlali Ekaterina Rodriguez Perez,
Wenxian Nie,
Robert A. Edwards,
James SinnettSmith,
Enrique Rozengurt
Publication year - 2012
Publication title -
american journal of physiology. gastrointestinal and liver physiology/american journal of physiology: gastrointestinal and liver physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.644
H-Index - 169
eISSN - 1522-1547
pISSN - 0193-1857
DOI - 10.1152/ajpgi.00522.2011
Subject(s) - downregulation and upregulation , cancer research , tumor necrosis factor alpha , myofibroblast , signal transduction , autocrine signalling , epidermal growth factor receptor , mapk/erk pathway , epidermal growth factor , cytokine , cyclin dependent kinase 8 , biology , microbiology and biotechnology , medicine , immunology , cancer , receptor , fibrosis , notch signaling pathway , biochemistry , gene
The myofibroblast has recently been identified as an important mediator of tumor necrosis factor-α (TNF-α)-associated colitis and cancer, but the mechanism(s) involved remains incompletely understood. Recent evidence suggests that TNF-α is a central regulator of multiple inflammatory signaling cascades. One important target of TNF-α may be the signaling pathway downstream of the epidermal growth factor receptor (EGFR), which has been associated with many human cancers. Here, we show that long-term exposure of 18Co cells, a model of human colonic myofibroblasts, with TNF-α led to a striking increase in cell surface EGFR expression, an effect that was completely inhibited by cycloheximide. Subsequent EGFR binding by EGF and heparin binding (HB)-EGF was associated with enhanced EGFR tyrosine kinase activity, prolonged ERK activation, and a significant increase in cyclooxygenase-2 (COX-2) expression compared with 18Co cells treated with EGF and HB-EGF alone. TNF-α also increased EGFR expression and signaling in primary myofibroblasts isolated from human colon tissue. TNF-α-induced upregulation of EGFR may be a plausible mechanism to explain the exaggerated cellular responsiveness that characterizes inflammatory bowel disease and that may contribute to a microenvironment that predisposes to colitis-associated cancer through enhanced COX-2 expression.