Insulin-like Growth Factor-1 Receptor Transactivation Modulates the Inflammatory and Proliferative Responses of Neurotensin in Human Colonic Epithelial Cells

Abstract

sion. 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. Neurotensin (NT)4 is a 13-amino acid neuropeptide initially isolated from the bovine hypothalamus by Carraway and Leeman (1) and is highly expressed in the gastrointestinal tract (2). NT modulates motility in the stomach, small bowel, and colon (3-5) and stimulates secretion in the dog jejunum (6) and human colonic mucosa (7,8). NT also stimulates growth and regeneration of the intestinal mucosa (9, 10) and has been implicated in the pathophysiology of colon cancer (11,12).Two G-protein-coupled receptors (GPCRs) have been described for NT: a high-affinity (NTR1) and a low-affinity (NTR2) receptor (13). A third, non-GPCR has also been identified (14). Several studies underlined the importance of NTR1 in several intestinal pathologic conditions. Administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic responses to stress (15, 16) and reduces colonic secretion and inflammation mediated by Clostridium difficile toxin A (17). Increased NTR1 expression is evident in the colonic mucosa during the course of acute colitis mediated by toxin A (17), in the colons of mice with experimental colitis (18), and in humans with inflammatory bowel disease (18). In a recent study, we also showed that involvement of NT in colonic inflammation may include direct stimulation of pro-inflammatory chemoattractant IL-8 transcription in colonic epithelial cells (19).NT stimulates several intracellular signaling events, as shown in human colonic and pancreatic cell lines expressing endogenous NTR1 (20, 21). These include increased intracellular calcium release (22, 23) and activation of the MAPK family member ERK1/2 in pancreatic MIA PaCa-2 cells (24), transformed colonic adenocarcinoma HT29 cells (24), and non-transformed human colonic epithelial NCM460 cells (19). Our recent studies indicate that NT also activates the NF-B pathway (19) and the Rho family of small GTPases (25,26). Two previous studies showed that pretreatment with PKC inhibitors reduces NT-induced ERK1/2 activation in CHO cells overexpressing NTR1 (24) and in pancreatic carcinoma PANC-1 cells expressing endogenous NTR1 (27). In contrast, our laboratory and Hassan et al. have found that EGF receptor (EGFR) transactivation is involved in NT-in-

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