Keratinocyte growth factor promotes goblet cell differentiation through regulation of goblet cell silencer inhibitor.

Abstract

Keratinocyte growth factor (KGF) is an epithelial cell-specific growth factor. Previous reports demonstrated that KGF induces differentiation of epithelial cells of gastrointestinal tract in vivo, especially goblet cell-specific lineage stimulation. Intestinal trefoil factor (ITF) is selectively expressed in intestinal goblet cells and its expression correlates with intestinal goblet cell differentiation. In this study, we analyzed the mechanism of KGF modulation of goblet cell differentiation through characterization of its effects on ITF gene expression. Subclone H2 of the human colonic epithelial cell line HT-29, which can be induced to intestinal goblet cells, was treated with KGF and characterized by Northern and Western blot analyses, transient transfection assays, and electrophoretic mobility shift assays (EMSAs). KGF promoted differentiation of H2 cells to goblet cells as reflected by induced ITF expression. Transient transfection assays revealed that KGF regulates mouse ITF transcription through the goblet cell silencer inhibitor (GCSI) element, which is essential for goblet cell-specific expression of ITF. EMSAs showed that KGF induces GCSI binding protein (GCSI-BP). KGF promotes goblet cell differentiation through the induction of GCSI-BP, a goblet cell-specific transcription factor. GCSI-BP may play a central role in intestinal goblet cell differentiation.