Cruickshank SM, Wakenshaw L, Cardone J, Howdle PD, Murray PJ, Carding SR. Evidence for the involvement of NOD2 in regulating colonic epithelial cell growth and survival. World J Gastroenterol 2008; 14(38): 5834-5841 [PMID: 18855982 DOI: 10.3748/wjg.14.5834]
Corresponding Author of This Article
Simon R Carding, Professor, The Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, United Kingdom. simon.carding@bbsrc.ac.uk
Article-Type of This Article
Basic Research
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World J Gastroenterol. Oct 14, 2008; 14(38): 5834-5841 Published online Oct 14, 2008. doi: 10.3748/wjg.14.5834
Evidence for the involvement of NOD2 in regulating colonic epithelial cell growth and survival
Sheena M Cruickshank, Louise Wakenshaw, John Cardone, Peter D Howdle, Peter J Murray, Simon R Carding
Sheena M Cruickshank, Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom; Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
Louise Wakenshaw, Simon R Carding, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom; The Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, United Kingdom
John Cardone, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
Peter D Howdle, Section of Medicine, Surgery & Anaesthesia, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom
Peter J Murray, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis TN 38105, United States
Author contributions: Cruickshank SM and Wakenshaw L contributed equally to this work; Cruickshank SM, Wakenshaw L and Cardone J performed research; Howdle PD and Carding SR contributed funding; Murray PJ contributed new reagents; Carding SR designed research; Cruickshank SM and Carding SR analyzed data and wrote the paper.
Supported by (in part) Grants from Action Medical Research (SRC, SMC); The Leeds Teaching Hospitals Charitable Foundation (SRC and PH), NIH (PJM); The European Union “Leonardo da Vinci” Scholarship Program (JC); BBSRC sponsored postgraduate studentship (LW); The American Lebanese Syrian Associated Charities (PJM)
Correspondence to: Simon R Carding, Professor, The Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, United Kingdom. simon.carding@bbsrc.ac.uk
Telephone: +44-1603-251410 Fax: +44-1603-255288
Received: December 21, 2007 Revised: July 14, 2008 Accepted: July 21, 2008 Published online: October 14, 2008
Abstract
AIM: To investigate the function of NOD2 in colonic epithelial cells (CEC).
METHODS: A combination of in vivo and in vitro analyses of epithelial cell turnover in the presence and absence of a functional NOD2 protein and, in response to enteric Salmonella typhimurium infection, were used. shRNA interference was also used to investigate the consequences of knocking down NOD2 gene expression on the growth and survival of colorectal carcinoma cell lines.
RESULTS: In the colonic mucosa the highest levels of NOD2 expression were in proliferating crypt epithelial cells. Muramyl dipeptide (MDP), that is recognized by NOD2, promoted CEC growth in vitro. By contrast, the growth of NOD2-deficient CECs was impaired. In vivo CEC proliferation was also reduced and apoptosis increased in Nod2-/- mice, which were also evident following enteric Salmonella infection. Furthermore, neutralization of NOD2 mRNA expression in human colonic carcinoma cells by shRNA interference resulted in decreased survival due to increased levels of apoptosis.
CONCLUSION: These findings are consistent with the involvement of NOD2 protein in promoting CEC growth and survival. Defects in proliferation by CECs in cases of CD may contribute to the underlying pathology of disrupted intestinal homeostasis and excessive inflammation.
