The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells
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...
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| Format: | Article |
| Language: | English |
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Wiley
2012-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2012/207398 |
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| _version_ | 1832549139809828864 |
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| author | Humberto B. Jijon Andre Buret Christina L. Hirota Morley D. Hollenberg Paul L. Beck |
| author_facet | Humberto B. Jijon Andre Buret Christina L. Hirota Morley D. Hollenberg Paul L. Beck |
| author_sort | Humberto B. Jijon |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ff1407a1833f4388a44786d93b33a9ef |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-ff1407a1833f4388a44786d93b33a9ef2025-02-03T06:12:10ZengWileyMediators of Inflammation0962-93511466-18612012-01-01201210.1155/2012/207398207398The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial CellsHumberto B. Jijon0Andre Buret1Christina L. Hirota2Morley D. Hollenberg3Paul L. Beck4Gastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, AB, T2N 1N4, CanadaGastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, AB, T2N 1N4, CanadaGastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, AB, T2N 1N4, CanadaGastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, AB, T2N 1N4, CanadaGastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, AB, T2N 1N4, CanadaTNF-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.http://dx.doi.org/10.1155/2012/207398 |
| spellingShingle | Humberto B. Jijon Andre Buret Christina L. Hirota Morley D. Hollenberg Paul L. Beck The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells Mediators of Inflammation |
| title | The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells |
| title_full | The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells |
| title_fullStr | The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells |
| title_full_unstemmed | The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells |
| title_short | The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells |
| title_sort | egf receptor and her2 participate in tnf α dependent mapk activation and il 8 secretion in intestinal epithelial cells |
| url | http://dx.doi.org/10.1155/2012/207398 |
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