The ErbB4 receptor tyrosine kinase regulates cell growth, survival, and differentiation in several tissues, but its role(s) in the gastrointestinal tract has not been reported. We tested the hypothesis that ErbB4 promotes intestinal cell survival and restitution following injury or inflammation.

ErbB4 expression in human inflammatory bowel disease was determined by immunohistochemistry. Mice were subjected to dextran sulfate sodium (DSS, 3%) colitis or injected with 10⁴ U tumor necrosis factor (TNF), and ErbB4 expression was quantified by immunohistochemistry and Western blot analysis of colon mucosal scrapings. Cultured young adult mouse colon (YAMC) cells were exposed to TNF, and then 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.

ErbB4 levels increased in Crohn's colitis and the colon epithelium of mice with DSS-induced colitis or injected with TNF. In YAMC cells, TNF induced ErbB4 messenger RNA, protein, and phosphorylation; nuclear factor κB activation also stimulated ErbB4 accumulation. ErbB4 siRNA knockdown sensitized YAMC 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 the antiapoptotic kinase 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.

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.