Heparin-binding epidermal-growth-factor-like growth factor gene expressionis induced by scrape-wounding epithelial cell monolayers: involvement of mitogen-activated protein kinase cascades

Peptide growth factors can promote the cell migration and proliferation tha t is needed to repair epithelia after mechanical or chemical injury. We rep ort here that scrape-wounding rat intestinal epithelial (RIE-1) cell monola yers caused a rapid increase in levels of heparin-binding epidermal-growth- factor-like growth factor (HB-EGF) mRNA, with a maximal response at approx. 1 h. Hybridization in situ showed that transcript induction occurred prima rily in cells at or near wound borders. The increase in HB-EGF mRNA was pre ceded by activation of the p42 mitogen-activated protein kinase (MAPK) in t he wounded cell cultures. Moreover, the induction of HB-EGF mRNA was blocke d by PD098059 and U0126, inhibitors that prevent the activation of p42/p44 MAPKs and extracellular activation and HB-EGF mRNA induction were inhibited by genistein, indicating a requirement for an upstream tyrosine kinase act ivity. In contrast, neither response was affected by inhibition of phosphoi nositide 3-kinase activity, down-regulation of protein kinase C, or disrupt ion of the actin cytoskeleton with cytochalasin B. We conclude that scrape- wounding epithelial cell monolayers induces HB-EGF mRNA expression by a mec hanism that most probably requires p42/p44 MAPK activation, although we can not exclude a role for ERK5. Our results suggest a physiological role for l ocally synthesized HB-EGF in promoting epithelial repair after injury.