Inflammatory bowel disease (IBD) is a common disorder characterized by chronic inflammation in the gastrointestinal tract. Current therapy for IBD focuses on drugs that inhibit inflammation. Paradoxically, it is well known that use of the anti-inflammatory prostaglandin synthesis inhibitors (non-steroidal anti-inflammatory drugs or NSAIDs) by individuals with IBD can actually activate quiescent disease and exacerbate established inflammation. The mechanism by which this occurs is unknown. We previously reported that mice with a targeted deletion of the gene for IL-10 (a key immune regulatory cytokine) develop spontaneous IBD due to the development of pathogenic Th1-type CD4+ T cells. We now report that treatment of IL-10-/- mice with NSAIDs results in the rapid development of severe intestinal inflammation. We hypothesize that absence of both prostaglandins and IL-10 results in enhanced activation of dendritic cells in the colon and mesenteric lymph nodes resulting in the rapid generation of pathogenic Th1-type CD4+ T cells. This hypothesis is supported by the following observations: (i) both prostaglandins and IL-10 are potent regulators of dendritic cells, which are the critical regulators of T cell differentiation. (ii) The development of inflammation in this novel animal model is dependent upon inhibition of prostaglandin production. (iii) Mesenteric lymph nodes from IL10-/- mice with NSAID-induced IBD have increased numbers of activated dendritic cells, and (iv) NSAID-induced IBD in IL10-/- mice requires the development of pathogenic T cells. The goal of this proposal is to determine the mechanisms by which prostaglandins regulate dendritic cell function and Th1 CD4 T cell generation using the novel animal model of IBD which we have developed, NSAID-treated ILl0-/- mice. We plan to test our central hypothesis by pursuing the following specific aims: (I) Determine the role of COX-1 and COX-2 derived prostaglandins in the regulation of intestinal inflammation in ILl0-/- mice; (II) Determine the interaction of IL-10 with COX-1 and COX-2 derived prostaglandins in the regulation of dendritic cell phenotype and function; and (III) Determine the effect of absence of IL-10 and prostaglandins in vivo on dendritic cell phenotype and function in the colon and mesenteric lymph nodes.
|DiMeo, Daniel; Tian, Jun; Zhang, Juan et al. (2008) Increased interleukin-10 production and Th2 skewing in the absence of 5-lipoxygenase. Immunology 123:250-62|
|Narushima, Seiko; DiMeo, Daniel; Tian, Jun et al. (2008) 5-Lipoxygenase-derived lipid mediators are not required for the development of NSAID-induced inflammatory bowel disease in IL-10-/- mice. Am J Physiol Gastrointest Liver Physiol 294:G477-88|