RRC ID 42197
Author Kitagawa K, Hamada Y, Kato Y, Nakai K, Nishizawa M, Ito S, Okumura T.
Title Epidermal growth factor and interleukin-1beta synergistically stimulate the production of nitric oxide in rat intestinal epithelial cells.
Journal Am J Physiol Gastrointest Liver Physiol
Abstract Epidermal 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-1beta 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-kappaB (IkappaB), NF-kappaB, and Akt, were analyzed. IL-1beta stimulated the degradation of IkappaB and the activation of NF-kappaB but had no effect on iNOS induction. EGF, which had no effect on the NF-kappaB 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-1beta stimulated synergistically the induction of iNOS, leading to the increased production of NO. Our results indicate that EGF and IL-1beta 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-kappaB through IkappaB kinase, respectively. Simultaneous addition of EGF and IL-1beta can enhance the production of NO, which may contribute to the cytoprotective effect of EGF against intestinal injury.
Volume 287(6)
Pages G1188-93
Published 2004-12-1
DOI 10.1152/ajpgi.00254.2004
PII 00254.2004
PMID 15271652
MeSH Animals Blotting, Northern Blotting, Western Cells, Cultured Chromones / pharmacology Drug Synergism Enzyme Inhibitors / pharmacology Epidermal Growth Factor / pharmacology* Epithelial Cells / drug effects Epithelial Cells / metabolism* ErbB Receptors / antagonists & inhibitors I-kappa B Proteins / metabolism Interleukin-1 / pharmacology* Intestinal Mucosa / metabolism* Intestines / cytology Intestines / drug effects Morpholines / pharmacology NF-kappa B / metabolism Nitric Oxide / biosynthesis* Nitric Oxide Synthase / antagonists & inhibitors Nitric Oxide Synthase / biosynthesis Nitric Oxide Synthase Type II Phosphoinositide-3 Kinase Inhibitors Protein-Serine-Threonine Kinases / biosynthesis Proto-Oncogene Proteins / biosynthesis Proto-Oncogene Proteins c-akt RNA, Messenger / biosynthesis Rats Staphylococcal Protein A / pharmacology
IF 3.725
Times Cited 8
Human and Animal Cells