The ErbB4 tyrosine kinase is highly expressed in colitis. In cell culture, its overexpression blocks tumor necrosis factor (TNF)‐induced colonocyte apoptosis, suggesting that induction in disease may be protective. In this study, we used the ErbB4‐specific ligand neuregulin‐4 (NRG4) to activate the receptor and define its role in cell survival.METHODSMouse colon epithelial cells expressing ErbB4 (MCE‐ErbB4) were exposed to TNF +/− NRG4. 6–8 week‐old C57Bl/6 mice were given TNF +/− NRG4 by i.p. injection. Cell counts in vitro were determined by MTS assay; signaling and apoptosis were assessed by western blot of cell lysates and mucosal scrapings or immunohistochemical analysis of formalin‐fixed tissue. Src and phosphatidylinositol 3‐kinase (PI3K) were inhibited with PP2 and LY294002, respectively.RESULTSNRG4 blocked TNF‐induced caspase‐3 cleavage and cell death in vitro (cell loss reduced by 64.8%; p<0.03), and inhibited TNF‐induced apoptosis (assessed by caspase‐3 cleavage) in vivo by 71% (p<0.05). NRG4‐treated MCE‐ErbB4 cells and colonic mucosal scrapings from NRG4‐injected mice showed elevated Akt and Src activation. In vitro inhibition of Src or PI3K reversed NRG4's protective effects on MCE‐ErbB4 cells.CONCLUSIONSErbB4 activation by NRG4 promotes colonocyte survival both in vitro and in vivo, likely through a Src‐ and PI3K‐dependent pathway. Exogenous NRG4 may be therapeutic for colitis.