Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Steven J McElroy; Stuart Hobbs; Michael Kallen; Noemi Tejera; Michael J Rosen; Anatoly Grishin; Poojitha Matta; Claus Schneider; Jeffrey Upperman; Henri Ford; D Brent Polk; Jörn-Hendrik Weitkamp

doi:10.1371/journal.pone.0038373

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Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Journal article

Open access

Peer reviewed

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Steven J McElroy, Stuart Hobbs, Michael Kallen, Noemi Tejera, Michael J Rosen, Anatoly Grishin, Poojitha Matta, Claus Schneider, Jeffrey Upperman, Henri Ford, …

PloS one, Vol.7(5), pp.e38373-e38373

2012

DOI: 10.1371/journal.pone.0038373

PMCID: PMC3364993

PMID: 22675459

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Abstract

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC.

Cell Line

Enterocytes - metabolism

Humans

Lipopolysaccharides - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Gene Expression Regulation - drug effects

Receptor, Epidermal Growth Factor - metabolism

Enterocytes - drug effects

Signal Transduction - drug effects

Cyclooxygenase 2 - genetics

Cyclooxygenase 2 - metabolism

Lipopolysaccharides - pharmacology

Protein Binding

p38 Mitogen-Activated Protein Kinases - metabolism

Epidermal Growth Factor - pharmacology

Matrix Metalloproteinases - metabolism

Enterocytes - enzymology

Details

Title: Subtitle: Transactivation of EGFR by LPS induces COX-2 expression in enterocytes
Creators: Steven J McElroy - Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
Stuart Hobbs
Michael Kallen
Noemi Tejera
Michael J Rosen
Anatoly Grishin
Poojitha Matta
Claus Schneider
Jeffrey Upperman
Henri Ford
D Brent Polk
Jörn-Hendrik Weitkamp
Resource Type: Journal article
Publication Details: PloS one, Vol.7(5), pp.e38373-e38373
DOI: 10.1371/journal.pone.0038373
PMID: 22675459
PMCID: PMC3364993
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: R21 AI083612 / NIAID NIH HHS P30 DK058404 / NIDDK NIH HHS T35 ES016534 / NIEHS NIH HHS 1T35 ES016534-01 / NIEHS NIH HHS R01AI014032 / NIAID NIH HHS K08DK083677 / NIDDK NIH HHS P30DK058404 / NIDDK NIH HHS K08 DK083677 / NIDDK NIH HHS R01 AI014032 / NIAID NIH HHS R01 DK056008 / NIDDK NIH HHS R01GM076592 / NIGMS NIH HHS R01DK54993 / NIDDK NIH HHS R01 DK054993 / NIDDK NIH HHS R21AI083612 / NIAID NIH HHS K08HD061607 / NICHD NIH HHS R01 GM076592 / NIGMS NIH HHS K08 HD061607 / NICHD NIH HHS R01DK56008 / NIDDK NIH HHS
Language: English
Date published: 2012
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics
Record Identifier: 9984093216502771

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