21212273

pubmed:Citation

8

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-?B-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-?B-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-?B-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-?B 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.

eng

IM

MEDLINE

1083-351X

Electronic

286

Y

pubmed-meshheading:21212273-Apoptosis, pubmed-meshheading:21212273-Bacterial Toxins, pubmed-meshheading:21212273-Cell Line, pubmed-meshheading:21212273-Colitis, pubmed-meshheading:21212273-Colon, pubmed-meshheading:21212273-Dextran Sulfate, pubmed-meshheading:21212273-Dose-Response Relationship, Drug, pubmed-meshheading:21212273-Enterotoxins, pubmed-meshheading:21212273-Enzyme Activation, pubmed-meshheading:21212273-Epithelial Cells, pubmed-meshheading:21212273-Gene Expression Regulation, pubmed-meshheading:21212273-Humans, pubmed-meshheading:21212273-Inflammation, pubmed-meshheading:21212273-Inflammatory Bowel Diseases, pubmed-meshheading:21212273-Interleukin-8, pubmed-meshheading:21212273-Intestinal Mucosa, pubmed-meshheading:21212273-NF-kappa B, pubmed-meshheading:21212273-Neurotensin, pubmed-meshheading:21212273-Phosphorylation, pubmed-meshheading:21212273-Protein Phosphatase 2, pubmed-meshheading:21212273-Proto-Oncogene Proteins c-akt, pubmed-meshheading:21212273-Proto-Oncogene Proteins pp60(c-src), pubmed-meshheading:21212273-Receptor, IGF Type 1, pubmed-meshheading:21212273-Receptors, Neurotensin, pubmed-meshheading:21212273-Time Factors, pubmed-meshheading:21212273-Tyrphostins

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

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