Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis

Koon, Hon–Wai; Kim, You Sun; Xu, Hua; Kumar, Aatish; Zhao, Dan; Καραγιαννίδης, Ιορδάνης; Dobner, Paul R.; Pothoulakis, Charalabos

doi:10.1073/pnas.0903499106

Cited by 63 publications

(68 citation statements)

References 35 publications

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“…The molecular mechanism inducing neurotensin expression in lung neoplasm remains unclear. As it was shown that neurotensin expression can be upregulated by inflammatory process and mediates proinflammatory cytokine release, such as interleukin-6 and interleukin-8 (28,29), we propose that neurotensin expression is induced and implicated in the pathogenesis of lung cancer due to chronic inflammation and neoplasia in the respiratory epithelium generated by tobacco carcinogens and metabolites. The evaluation of neurotensin expression in premalignant lesions will settle this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

Alifano

Souazé

Dupouy

et al. 2010

Clinical Cancer Research

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Purpose: This study aimed to investigate the role of the neurotensin/neurotensin receptor I (NTSR1) complex in non-small cell lung cancer (NSCLC) progression.Experimental Design: The expression of neurotensin and NTSR1 was studied by transcriptome analysis and immunohistochemistry in two series of 74 and 139 consecutive patients with pathologic stage I NSCLC adenocarcinoma. The findings were correlated with clinic-pathologic features. Experimental tumors were generated from the malignant human lung carcinoma cell line A459, and a subclone of LNM35, LNM-R. The role of the neurotensin signaling system on tumor growth and metastasis was investigated by small hairpin RNA-mediated silencing of NTSR1 and neurotensin.Results: Transcriptome analysis carried out in a series of 74 patients showed that the positive regulation of NTSR1 put it within the top 50 genes related with relapse-free survival. Immunohistochemistry revealed neurotensin-and NTSR1-positive staining in 60.4% and 59.7% of lung adenocarcinomas, respectively. At univariate analysis, NTSR1 expression was strongly associated with worse 5-year overall survival rate (P = 0.0081) and relapse-free survival (P = 0.0024). Multivariate analysis showed that patients over 65 years of age (P = 0.0018) and NTSR1 expression (P = 0.0034) were independent negative prognostic factors. Experimental tumor xenografts generated by neurotensin-and NTSR1-silenced human lung cancer cells revealed that neurotensin enhanced primary tumor growth and production of massive nodal metastasis via autocrine and paracrine regulation loops.Conclusion: NTSR1 expression was identified as a potential new prognostic biomarker for surgically resected stage I lung adenocarcinomas, as NTSR1 activation was shown to participate in lung cancer progression.

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Section: Discussionmentioning

confidence: 99%

Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

Alifano

Souazé

Dupouy

et al. 2010

Clinical Cancer Research

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“…We also present evidence that NT-associated phosphorylation of IGF-1R involves the high-affinity NT receptor NTR1 and is linked to Akt phosphorylation, cell proliferation, and NF-B-driven IL-8 transcription. Because previous results from our laboratory and others have demonstrated an important role for NT and NTR1 in the pathophysiology of acute ileitis (17), acute colitis (44), and mucosal healing following colitis (18), IGF-1R transactivation in response to NT/ NTR1 coupling may play an important role in the pathophysiology of intestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Bakirtzi

Zhan

et al. 2011

Journal of Biological Chemistry

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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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“…Telmisartan treatment contributed to inhibit the neurotensin/miR-155 signaling pathway in the MAT, suggesting that this pathway could contribute to attenuate the MAT alteration and gut inflammation. Indeed, it was previously demonstrated that neurotensin level is chronically increased in fat during the course of experimental colitis [29]. In the same study, the authors also demonstrated that neurotensin could induce the secretion of IL-6 and the migration of macrophages [29].…”

Section: Discussionmentioning

confidence: 86%

“…In an experimental colitis induced by dextran sodium sulfate (DSS), colonic neurotensin expression is elevated [28]. In addition, increased neurotensin expression is found in adipocytes of MAT of mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis [29]. Additionally, neurotensin can directly stimulate the expression of microRNA-155 (miR-155) [30] which regulates the intestinal immune function [31] and is effective in inhibition of adipocyte differentiation [32][33][34].…”

Section: Introductionmentioning

confidence: 98%