The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF.
OBJECTIVE
The ErbB4 receptor tyrosine kinase regulates cell growth, survival, and differentiation in several tissues, but its role in the gastrointestinal tract has not been reported. We tested the hypothesis that ErbB4 promotes intestinal cell survival and restitution following injury or inflammation.


METHODS
ErbB4 expression in human inflammatory bowel disease was determined by immunohistochemistry. Mice were subjected to dextran sulfate sodium (DSS, 3%) colitis or injected with tumor necrosis factor (TNF), and ErbB4 expression was quantified by immunohistochemistry and Western blot. Cultured young adult mouse colon (YAMC) cells were exposed to TNF, and ErbB4 messenger RNA, protein, and phosphorylation levels were measured. Cells transfected with ErbB4 small interfering RNA (siRNA), or over expressing ErbB4, were subjected to wound healing and apoptosis assays.


RESULTS
ErbB4 levels increased in Crohn's colitis and the colon epithelium of mice with DSS colitis or injected with TNF. In YAMC cells, TNF induced ErbB4 messenger RNA, protein, and phosphorylation; nuclear factor kappaB activation also stimulated ErbB4 accumulation. ErbB4 siRNA sensitized cells to TNF-stimulated apoptosis, while over expression blocked apoptosis induced by TNF plus cycloheximide. Additionally, ErbB4 siRNA decreased YAMC cell wound healing. ErbB4 knockdown attenuated, while over expression elevated, phosphorylation of Akt in response to TNF. Inhibition of the phosphatidylinositol 3-kinase/Akt signaling cascade reversed the ability of ErbB4 over expression to protect from cytokine-induced apoptosis.


CONCLUSIONS
ErbB4 expression and signaling are key elements for TNF responses in vivo and in cell culture, protecting intestinal epithelial cells from apoptosis in the inflammatory environment, possibly through Akt activation.
Frey
Mark R
MR
Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696, USA.
Edelblum
Karen L
KL
Mullane
Matthew T
MT
Liang
Dongchun
D
Polk
D Brent
DB
D000818:Animals; D002470:Cell Survival; D003106:Colon / Q000166:cytology*; D003424:Crohn Disease / Q000378:metabolism; D066246:ErbB Receptors / Q000032:analysis / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014945:Wound Healing
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D051057:Proto-Oncogene Proteins c-akt