Role of the Endogenous Cannabinoid System in the Human Gastrointestinal Tract

Dr. Karen L Wright

Department of Pharmacy and Pharmacology/University of Bath, UK

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, affect more than 100,000 people in the UK. They can give rise to symptoms of bloody diarrhoea, abdominal pain and weight loss. These diseases are characterised by recurring bouts of these symptoms over many years. Such long-term inflammation acts as a risk factor for bowel cancer. The cause of inflammatory bowel disease remains unclear and there is no cure. Drug therapy (such as steroid use) has an anti-inflammatory effect through non-specific generalised immunosuppression.

A family of molecules, termed endocannabinoids, occur naturally in the body. During the last few years, the potential medicinal use of Cannabis in human diseases has focused much attention on the system inherent in the body that responds to both plant-derived and endogenous cannabinoids. Endocannabinoids have modulatory effects on the immune system and this may have therapeutic implications for inflammatory conditions, such as IBD. How endocannabinoids affect cells in the colon is the primary purpose of research being carried out by myself with Prof Ward and in collaboration with gastroenterologists at the Royal United Hospital. Using human colonic tissue and cells we have established the existence of a functioning endocannabinoid system in the colon and that cannabinoids are involved in wound repair of the gut lining. We are currently investigating the mechanisms of this process using adult progenitor cells that are normally involved in restitution and how cannabinoids and other phospholipids impact on their migration, proliferation and differentiation. This research will contribute to our understanding of the normal regulation of this system and may lead to novel therapeutic targets for IBD.

Cannabinoid receptor expression in the tubular epithelium of normal human colonic tissue:

Karen Coopman, Laura D. Smith, Karen L. Wright and Stephen G. Ward. (2007) Temporal variation in CB2R levels following T lymphocyte activation: Evidence that cannabinoids modulate CXCL12-induced chemotaxis. Int. Immunopharmacol. 7(3):360-371.

Orr Ofek, Meliha Karsak, Nathalie Leclerc, Meirav Fogel, Baruch Frenkel, Karen Wright, Joseph Tam, Malka Attar-Namdar, Vardit Kram, Esther Shohami, Raphael Mechoulam, Andreas Zimmer, and Itai Bab (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. PNAS, 103(3), 696-701.

Kouroumalis A, Aptel H, Nibbs RJ, Wright KL, Kolios G, Ward SG. (2005) The chemokines CXCL9, CXCL10 and CXCL11 differentially stimulate G?i-independent signalling and actin responses in human intestinal myofibroblasts. J. Immunol. 175 (8), 5403-5411.

Wright KL, Rooney N, Feeney M, Tate J, Robertson DAF, Welham MJ and Ward SG. (2005) Differential expression of functional cannabinoid receptors in human colonic epithelium: evidence that cannabinoids promote wound healing. Gastroenterology 129(2), 437-453.

Patel K, Wright KL, Whittaker P, Chakravarty P, Watson M and Ward SG. (2005) Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPAR? agonists: evidence for disparate functional effects which are independent of NF-kappa B and PPAR gamma. Cell Sig. 17(9), 1098-110.

Wright KL, Weaver SA, Patel K, Coopman K, Feeney M, Kolios G, Robertson DAF and Ward SG. (2004) Differential regulation of prostaglandin E biosynthesis by interferon-gamma in epithelial cells. Br. J. Pharmacol. 141(7), 1091-1097.

Curnock AP, Sotsios Y, Wright KL and Ward SG. (2003) Optimal Chemotactic Responses of Leukemic T Cells to Stromal Cell-Derived Factor-1 Requires the Activation of Both Class IA and IB Phosphoinositide 3-Kinases. J Immunol. 170(8), 4021-30.

Freeburn RW, Wright KL, Burgess SJ, Astoul E, Cantrell DA and Ward SG. (2002) Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors. J Immunol. 169(10), 5441-50.

Weaver SA, Pia Russo M, Wright KL, Kolios G, Jobin C, Robertson DAF and Ward SG. (2001) Regulatory role of phosphatidylinositol 3-kinase on TNF alpha-induced cyclooxygenase-2 expression in colonic epithelial cells. Gastroenterology, 120(5), 1117-1127.

Wright KL and Ward SG. (2000) Interactions between phosphatidylinositol 3-kinase and nitric oxide: explaining the paradox. Minireview Mol. Cell. Biol. Res. Commun., 4(3), 137-143.

Kolios G, Wright KL, Linehan JD, Robertson DAF and Westick J. (2000) Interleukin-13 inhibits nitric oxide production in human colonic mucosa. Hepato-Gastroenterology 47, 714-717.

Wright KL, Kolios G, Westwick J and Ward SG. (1999) Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric oxide formation: evidence for an IL-13-driven PI3-kinase-dependent survival mechanism. J. Biol. Chem. 276, 17193-17201.

Kolios, G., Wright, K.L., Jordan, N.J., Leithead, J.B., Robertson, D.A.F. and Westwick, J. (1999) C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocyte-derived cytokines. Eur. J. Immunol. 29, 530-536.

Wright, K., Ward, S.G., Kolios, G. and Westwick, J. (1997) Activation of phosphatidylinositol 3-kinase by interleukin-13 - An inhibitory signal for inducible nitric-oxide synthase expression in the epithelial, cell line HT-29. J. Biol. Chem., 272, 12626-12633.

Kolios G, Wright KL, Jordan NJ, Leithead JB, Murphy CT, Robertson DAF and Westwick J. (1997) Regulation of inflammatory mediator production in human colonic epithelial cells. Hell. J. Gastroenterol. 10, 135-147.

Department of Pharmacy and Pharmacology
University of Bath (7 West 4.1 )
Claverton Down
Bath
BA2 7AY
ENGLAND