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

McElroy, Steven J., Hobbs, Stuart, Kallen, Michael, Tejera Hernandez, Noemi, Rosen, Michael J., Grishin, Anatoly, Matta, Poojitha, Schneider, Claus, Upperman, Jeffrey, Ford, Henri, Polk, D. Brent and Weitkamp, Jörn-Hendrik (2012) Transactivation of EGFR by LPS induces COX-2 expression in enterocytes. PLoS One, 7 (5). ISSN 1932-6203

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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.

Item Type:	Article
Additional Information:	© 2012 McElroy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords:	cell line,cyclooxygenase 2,enterocytes,epidermal growth factor,extracellular signal-regulated map kinases,gene expression regulation,humans,lipopolysaccharides,matrix metalloproteinases,protein binding,receptor, epidermal growth factor,signal transduction,p38 mitogen-activated protein kinases
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Noemi Tejera Hernandez
Date Deposited:	01 May 2013 12:20
Last Modified:	18 Nov 2022 16:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/39597
DOI:	10.1371/journal.pone.0038373

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