Cytokine modulation of intestinal epithelial cell restitution: Central role of transforming growth factor β

Background: After various forms of superficial injury, mucosal integrity is re-established by rapid migration of epithelial cells across the wound margins in a process termed restitution. The aim of the present study was to assess the role of several regulatory peptides produced within the intestinal mucosa in epithelial restitution. Methods: The effects of various cytokines and peptide growth factors were studied in an in vitro model of intestinal epithelial restitution. Standard "wounds" were established in confluent monolayers of the intestinal cell line IEC-6, and migration was quantitated in the presence or absence of the physiologically relevant cytokines transforming growth factor (TGF)-α, epidermal growth factor (EGF), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon gamma (IFN-γ), and platelet-derived growth factor (PDGF). Results: Four factors (TGF-α, EGF, IL-1β, and IFN-γ) enhanced epithelial cell restitution by 2.3-fold to 5.5-fold. In contrast, IL-6, TNF-α, PDGF, and an endotoxin lipopolysaccharide had no effect on cell migration. Enhancement of restitution was independent of proliferation. The restitution-promoting cytokines TGF-α, EGF, IL-1β, and IFN-γ increase the production of bioactive TGF-β1 peptide in wounded IEC-6 cell monolayer. The promotion of IEC-6 restitution by various cytokines could be completely blocked by addition of immunoneutralizing anti-TGF-β1. Conclusions: These findings suggest that various cytokines that are expressed in intestinal mucosa promote epithelial restitution after mucosal injury through increased production of bioactive TGF-β1 in epithelial cells.