LAUSR

ABSTRACT Intestinal wound healing depends on the precise balance of restitution, proliferation, and differentiation of intestinal epithelial cells (IECs). In a previous study, we revealed that IEC proliferation was suppressed under histidine deficiency. However, the role of histidine in cell restitution is poorly understood. Meanwhile, addition of arginine to basal medium enhanced IEC restitution after wounding. However, there are no reports on whether histidine or arginine deficiency influences IEC restitution. We examined the roles of histidine and arginine in IEC restitution using the rat intestinal epithelial cell‐6 (IEC‐6) cell line. In the present study, the cell restitution in medium lacking histidine (&Dgr;His) or arginine (&Dgr;Arg) was most greatly decreased among media lacking each of the 20 intravital amino acids, compared with that in medium containing all 20 intravital amino acids (Full). TGF‐&bgr;1 is a known repair factor for cell restitution. The TGF‐&bgr;1 extracellular concentration and Tgf‐&bgr;1 mRNA level were decreased in &Dgr;His or &Dgr;Arg. Supplementation of 10&mgr;M histidine to &Dgr;His or 50&mgr;M arginine to &Dgr;Arg recovered the decreases in both cell restitution and TGF‐&bgr;1 extracellular concentration. Phosphorylation of Smad2, a signaling molecule for the TGF‐&bgr; pathway, was decreased in &Dgr;His or &Dgr;Arg. Additionally, the phosphorylation of mammalian target of rapamycin, p70 ribosomal protein S6 kinase and extracellular signal‐regulated kinase were decreased in &Dgr;His or &Dgr;Arg. The present findings suggested that deletion of histidine or arginine led to a decrease in IEC restitution through a decrease in TGF‐&bgr;1. We revealed that histidine and arginine play important roles in IEC restitution.