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

• Published in: PloS one Vol. 7; no. 5; p. e38373
• Main Authors: McElroy, Steven J, Hobbs, Stuart, Kallen, Michael, Tejera, Noemi, Rosen, Michael J, Grishin, Anatoly, Matta, Poojitha, Schneider, Claus, Upperman, Jeffrey, Ford, Henri, Polk, D Brent, Weitkamp, Jörn-Hendrik
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.05.2012; Public Library of Science (PLoS)
• Subjects: Activation; Autophagy; Bacteria; Biology; Celecoxib; Cell Line; Cell proliferation; Cell survival; Children & youth; COX-2 inhibitors; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Enterocolitis; Enterocytes; Enterocytes - drug effects; Enterocytes - enzymology; Enterocytes - metabolism; Enzyme inhibitors; Epidermal growth factor; Epidermal Growth Factor - pharmacology; Epidermal growth factor receptors; Epidermal growth factors; Epithelial cells; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Flora; Gastrointestinal diseases; Gene Expression Regulation - drug effects; Health aspects; Hospitals; Humans; Infants; Inflammation; Inflammatory response; Intestine; Kinases; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; MAP kinase; Matrix metalloproteinase; Matrix Metalloproteinases - metabolism; Medicine; Metabolic pathways; Metalloproteinase; Mitogens; Morbidity; Necrosis; Necrotizing enterocolitis; Newborn babies; p38 Mitogen-Activated Protein Kinases - metabolism; Pathogenesis; Pediatrics; Premature infants; Protein Binding; Protein kinases; Protein-tyrosine kinase; Receptor, Epidermal Growth Factor - metabolism; Rodents; Signal Transduction - drug effects; Signaling; Stimulation; Surgery; TLR4 protein; Toll-like receptors; Tyrosine; Los Angeles California; California; United States > US; Tennessee; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0038373

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.