Intestinal inflammation can occur in a number of pathologies, perhaps the most serious of which is inflammatory bowel disease (IBD). IBD is an umbrella term used to describe two distinct clinical conditions, ulcerative colitis (UC) and Crohn's disease (CD). UC and CD are both chronic digestive diseases resulting from an abnormal immune system response to stimuli in the digestive tract. UC primarily occurs in the colon and causes inflammation in the upper layers of the large intestine, while CD usually appears in the small intestine and causes inflammation deeper within the wall of the intestine. IBD usually begins at a young age, is medically incurable, often requires surgery, and can recur over a lifetime. The cause of IBD is unknown although it is generally considered that a genetic predisposition contributes to an unregulated intestinal immune response to an environmental, dietary, or infectious agent. In 2001, the number of prevalent cases of IBD has been estimated to have totaled over 1.5 million in the major pharmaceutical markets. Currently in excess of $0.5 billion, IBD related sales have been forcasted to increase by 3-10% each year for the next 5 years. Current treatment options are sub-optimal and the present focus in on the identification of inflammatory mediators involved in IBD. A greater understanding of inflammatory pathways and new "biologic agents" that will emerge from this knowledge will expand the IBD market and provide improved options for the patient. The neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) have been extensively implicated in a number of disease states (see our dossier "Tachykinins receptor antagonists: One therapeutic class for multiple indications?") as well as IBD. SP is known to stimulate production of interleukin (IL)-6 and IL-8 via activation of p38MAPK and NFkappaB, respectively. However, the signaling mechanisms by which SP-NK-1R interaction induces NFkappaB activation and IL-8 expression are still not clear. IBD field-leaders have recently addressed this issue demonstrating an involvement of Rho family proteins. Specifically SP rapidly activates RhoA, Rac1 and Cdc42, and stimulates IL-8 promoter activity and IL-8 secretion in human colonic epithelial cells. In addition, inhibition of endogenous RhoA, Rac1 and Cdc42 significantly decreases SP-induced IL-8 secretion and IL-8 promoter activity. These data suggest that inhibitors of Rho family small GTPases may offer a novel and rational approach to inflammatory conditions such as IBD.

Entry date October, 2002

Adapted from Pothoulakis et al, Biochem J 2002 Aug 8

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