On the regulation and effects of chronic inflammation in inflammatory bowel disease

Sammanfattning: Inflammatory bowel disease is thought to result from the inappropriate and ongoing activation of the mucosal immune system driven by the presence of normal luminal flora. In this process monocytes/macrophages contribute to and maintain chronic inflammation by being both regulatory and effector cells. This study aimed at exploring the effects and regulation of chronic inflammation in inflammatory bowel disease (IBD) at three different levels, (i) patient outcome by the analysis of the effects of inflammation on trombogenesis and dysplasia, (ii) cellular functions, by examination of inflammatory molecules in leukocytes derived from patients with IBD, and (iii) potential future treatment, by evaluation of the anti-inflammatory properties of statins on monocytes. By using age as a marker of thrombogenesis we show that patients with IBD had thrombosis earlier in life than patients not suffering from IBD, indicating an increased thrombotic risk. Increased disease activity probably contributes to the risk and a suggested mechanism in mediating thrombosis is involvement of pro-inflammatory cytokines, shifting the intravascular environment from haemodynamic stable to a procoagulative state. We observed no association between IBD and the most frequent hereditary prothrombotic conditions. In patients with ulcerative colitis, we detected an increased number of activated colonic eosinophils containing transforming growth factor-alpha (TGF-alpha). Eosinophils containing TGF-alpha may play both physiological and pathophysiological roles. Actions intended to enhance mucosal protection and facilitate repair during active inflammation could instead, during subclinical, chronic inflammation, lead to a transformation into dysplasia and the development of malignancy in long-standing ulcerative colitis. By assessment of circulating monocytes from patients with Crohn’s disease, we show that these monocytes are sensitized to chemotaxis prior to mucosal invasion. Furthermore, we show that it is possible to regulate the inflammatory response ex vivo in monocytes by statins. We demonstrate that pravastatin and atorvastatin not only lower cholesterol synthesis and lipid accumulation in human monocyte cultures, but also potently inhibit the generation of pro-inflammatory mediators and oxygen consumption in activated monocytes. Moreover, we found that atorvastatin transcriptionally activates peroxisome proliferator-activated receptor gamma in human monocytes, suggesting that statins may control inflammatory responses by the regulation of intracellular lipid homeostasis.