Insulin-like growth factor-1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells

J Biol Chem. 2011 Feb 25;286(8):6092-9. doi: 10.1074/jbc.M110.192534. Epub 2011 Jan 6.

Abstract

Neurotensin (NT) is a gastrointestinal neuropeptide that modulates intestinal inflammation and healing by binding to its high-affinity receptor NTR1. The dual role of NT in inflammation and healing is demonstrated in models of colitis induced by Clostridium difficile toxin A and dextran sulfate sodium, respectively, and involves NF-κB-dependent IL-8 expression and EGF receptor-mediated MAPK activation in human colonocytes. However, the detailed signaling pathways involved in these responses remain to be elucidated. We report here that NT/NTR1 coupling in human colonic epithelial NCM460 cells activates tyrosine phosphorylation of the insulin-like growth factor-1 receptor (IGF-1R) in a time- and dose-dependent manner. NT also rapidly induces Src tyrosine phosphorylation, whereas pretreatment of cells with the Src inhibitor PP2 before NT exposure decreases NT-induced IGF-1R phosphorylation. In addition, inhibition of IGF-1R activation by either its specific antagonist AG1024 or siRNA against IGF-1 significantly reduces NT-induced IL-8 expression and NF-κB-dependent reporter gene expression. Pretreatment with AG1024 also inhibits Akt activation and apoptosis induced by NT. Silencing of Akt expression by siRNA also substantially attenuates NT-induced IL-8 promoter activity and NF-κB-dependent reporter gene expression. This is the first report to indicate that NT transactivates IGF-1R and that this response is linked to Akt phosphorylation and NF-κB activation, contributing to both pro-inflammatory and tissue repair signaling pathways in response to NT in colonic epithelial cells. We propose that IGF-1R activation represents a previously unrecognized key pathway involved in the mechanisms by which NT and NTR1 modulate colonic inflammation and inflammatory bowel disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Bacterial Toxins / toxicity
  • Cell Line
  • Colitis / chemically induced
  • Colitis / metabolism
  • Colitis / pathology
  • Colon / metabolism*
  • Colon / pathology
  • Dextran Sulfate / adverse effects
  • Dextran Sulfate / pharmacology
  • Dose-Response Relationship, Drug
  • Enterotoxins / toxicity
  • Enzyme Activation / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / metabolism
  • Inflammatory Bowel Diseases / metabolism
  • Interleukin-8 / biosynthesis
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • NF-kappa B / metabolism
  • Neurotensin / metabolism
  • Neurotensin / pharmacology*
  • Phosphorylation / drug effects
  • Protein Phosphatase 2 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptor, IGF Type 1 / agonists
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, Neurotensin / genetics
  • Receptors, Neurotensin / metabolism
  • Time Factors
  • Tyrphostins / pharmacology

Substances

  • Bacterial Toxins
  • CXCL8 protein, human
  • Enterotoxins
  • Interleukin-8
  • NF-kappa B
  • Receptors, Neurotensin
  • Tyrphostins
  • neurotensin type 1 receptor
  • tcdA protein, Clostridium difficile
  • tyrphostin AG 1024
  • Neurotensin
  • Dextran Sulfate
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins pp60(c-src)
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 2