Epithelial regeneration is a key process for the recovery from ulcerative 
colitis (UC). Here we demonstrate that a disintegrin and metalloproteinase-17 
(ADAM17), a main sheddase for tumor necrosis factor (TNF)-α, is essential for 
defensive epithelial properties against UC by promoting epithelial cell growth 
and goblet cell differentiation in mouse and human. Mice with systemic deletion 
of Adam17 developed severe dextran sulfate sodium-induced colitis when compared 
to mice with myeloid cell Adam17 deletion or control littermates. ADAM17 was 
predominantly expressed by regenerating epithelia in control mice, and its loss 
or inhibition attenuated epidermal growth factor receptor (EGFR) activation, 
epithelial proliferation, mucus production and barrier functions. Conversely, 
ectopic EGFR stimulation promoted epithelial regeneration thereby partially 
rescuing the severe colitis caused by ADAM17 deficiency. In UC patients, 
epithelial ADAM17 expression positively correlated with both cell proliferation 
and goblet cell number. These findings suggest that maintaining ADAM17-EGFR 
epithelial signaling is necessary for the recovery from UC and would be 
beneficial to therapeutic strategies targeting ADAM17-mediated TNF-α shedding.