Mechanisms of Active Intestinal Inflammation and Potential Down-Regulation Via Lipoxins

Abstract

Chronic inflammatory diseases of the intestine (i.e. Crohn’s and chronic ulcerative colitis-collectively known as inflammatory bowel disease [IBDI) are a very significant public health problem in the United States and other industrialized nations. Thus, effort has been made toward understanding the biological mechanisms that regulate such inflammation. Largely, these efforts have focused on identifying the mechanisms that mediate activation of inflammation and have succeeded in identifying a variety of signaling pathways by which a wide range of agonists can activate a mucosal immune inflammatory response. Playing a central role in many of these pathways is the intestinal epithelium, which serves as a barrier to, and interfaces with the outside world. However, recent studies have shown that not only can some agonists activate pro-inflammatory signals in intestinal epithelial cells, but other agonists can activate “anti-inflammatory” signals in these cells that dampen the responses to pro-inflammatory agonists. One such anti-inflammatory agonist is the eicosanoid lipoxin A4 (LXA₄). Specifically, LXA₄its epimer 15-LXA₄and their analogs potently down-regulate defining and causative events of intestinal inflammation in an in vitro model. These compounds are now being tested for their ability to down-regulate inflammation in mouse models of colitis and may ultimately prove to be of significant benefit to individuals suffering from debilitating chronic inflammatory intestinal disorders.