Epidermal growth factor and interleukin-1β synergistically stimulate the production of nitric oxide in rat intestinal epithelial cells

Abstract

growth factor (EGF) is one of the trophic factors for intestinal adaptation after small bowel transplantation (SBT). A recent report indicates that nitric oxide (NO) has cytoprotective effects on bacterial translocation (BT) after SBT. We hypothesized that EGF stimulates the expression of the inducible NO synthase (iNOS) gene in the graft after SBT, followed by increased production of NO, resulting in the decrease of BT. Intestinal epithelial cells (IEC)-6 were treated with EGF and/or IL-1␤ in the presence and absence of phosphatidylinositol 3-kinase (PI3-kinase) and EGF receptor kinase inhibitors (LY-294002 and tyrphostin A25). The induction of NO production and iNOS and its signal molecules, including the inhibitory protein of NF-B (IB), NF-B, and Akt, were analyzed. IL-1␤ stimulated the degradation of IB and the activation of NF-B but had no effect on iNOS induction. EGF, which had no effect on the NF-B activation and iNOS induction, stimulated the upregulation of type 1 IL-1 receptor (IL-1R1) through PI3-kinase/Akt. Simultaneous addition of EGF and IL-1␤ stimulated synergistically the induction of iNOS, leading to the increased production of NO. Our results indicate that EGF and IL-1␤ stimulate two essential signals for iNOS induction in IEC-6 cells: the upregulation of IL-1R1 through PI3-kinase/Akt and the activation of NF-B through IB kinase, respectively. Simultaneous addition of EGF and IL-1␤ can enhance the production of NO, which may contribute to the cytoprotective effect of EGF against intestinal injury. inducible nitric oxide synthase; nuclear factor-B; phosphatidylinositol 3-kinase; Akt; type 1 interleukin-1 receptor.

Heparin-Binding Epidermal Growth Factor-Like Growth Factor Inhibits Cytokine-Induced NF-κB Activation and Nitric Oxide Production via Activation of the Phosphatidylinositol 3-Kinase Pathway

“…HB-EGF appears to differ from EGF in its NO-inhibitory effects in intestinal epithelial cells in that EGF and IL-1␤ have been found to synergistically stimulate iNOS expression and NO production in intestinal epithelial cells (41).…”

Ileal perforation induced by acute radiation injury under gefitinib treatment

“…Phosphorylation of EGFR activates its downstream pathways and is indispensable for wound healing. Recently the role of pEGFR has been revealed not only in the wound healing of skin tissues [6], but also in the regeneration of the gastrointestinal mucosa [7] and ulcer repair [8]. On the other hand, the gastrointestinal side effects of EGFR-TKIs include diarrhea and nausea.…”