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

被引:31
|
作者
Jijon, Humberto B. [1 ]
Buret, Andre [1 ]
Hirota, Christina L. [1 ]
Hollenberg, Morley D. [1 ]
Beck, Paul L. [1 ]
机构
[1] Univ Calgary, Hlth Sci Ctr, Gastrointestinal Res Grp, Calgary, AB T2N 1N4, Canada
关键词
EPIDERMAL-GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; INFLAMMATORY-BOWEL-DISEASE; TYROSINE KINASE; PROTEIN-KINASE; KAPPA-B; COLON-CARCINOMA; CANCER; TRANSACTIVATION; PHOSPHORYLATION;
D O I
10.1155/2012/207398
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
TNF-alpha 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-alpha. 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-alpha; treatment of IECs with batimastat suppressed TGF-alpha release and immunoneutralization of TGF-alpha resulted in decreased EGFR and ERK phosphorylations. TNF-alpha 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-alpha-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.
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页数:12
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