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Mediators of Inflammation
Volume 2012 (2012), Article ID 207398, 12 pages
http://dx.doi.org/10.1155/2012/207398
Research Article

The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells

Gastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, AB, Canada T2N 1N4

Received 7 January 2012; Accepted 24 July 2012

Academic Editor: Thirumala-Devi Kanneganti

Copyright © 2012 Humberto B. Jijon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

TNF- 𝛼 activates multiple mitogen-activated protein kinase (MAPK) cascades in intestinal epithelial cells (IECs) leading to the secretion of interleukin 8 (IL-8), a neutrophil chemoattractant and an angiogenic factor with tumor promoting properties. As the epidermal growth factor receptor (EGFR) is a known transducer of proliferative signals and a potent activator of MAPKs, we hypothesized that the EGFR participates in TNF-dependent MAPK activation and IL-8 secretion by intestinal epithelial cells (IECs). We show that the EGFR is tyrosine-phosphorylated following treatment of IECs (HT-29 and IEC-6) with TNF- 𝛼 . This requires EGFR autophosphorylation as it was blocked by the EGFR kinase inhibitor AG1478. Autophosphorylation was also inhibited by both a Src-kinase inhibitor and the metalloproteinase inhibitor batimastat. TNF treatment of IECs resulted in the accumulation of soluble TGF- 𝛼 ; treatment of IECs with batimastat suppressed TGF- 𝛼 release and immunoneutralization of TGF- 𝛼 resulted in decreased EGFR and ERK phosphorylations. TNF- 𝛼 treatment of IECs resulted in an association between EGFR and HER2 and inhibition of HER2 using a specific inhibitor AG879 in combination with AG1478-suppressed TNF- 𝛼 -dependent ERK phosphorylation and IL-8 release. Downregulation of HER2 via siRNA resulted in a significant decrease in ERK phosphorylation and a 50% reduction in IL-8 secretion.