title: Insulin-like growth factor-1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells.
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.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 022115, USA. dzhao@bidmc.harvard.edu
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Bakirtzi
authors.forename: Yanai
authors.initials: Y
authors.lastname: Zhan
authors.forename: Huiyan
authors.initials: H
authors.lastname: Zeng
authors.forename: Hon Wai
authors.initials: HW
authors.lastname: Koon
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000633:toxicity; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009496:Neurotensin / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D001427:Bacterial Toxins; C508606:CXCL8 protein, human; D004768:Enterotoxins; D016209:Interleukin-8; D016328:NF-kappa B; D018028:Receptors, Neurotensin; D020032:Tyrphostins; C114036:neurotensin type 1 receptor; C041348:tcdA protein, Clostridium difficile; C447031:tyrphostin AG 1024; D009496:Neurotensin; D016264:Dextran Sulfate; D017526:Receptor, IGF Type 1; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2