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Intestinal mucositis is a serious complication of cancer chemotherapy and radiotherapy; it frequently compromises treatment and dramatically reduces the quality of life of patients. Different approaches to limit the damage to the intestine during anti-cancer therapy have been largely ineffective due to insufficient knowledge of the mechanism of mucositis development. This study aimed to define the role of TLR-2 and TLR-9 in the modulation of small intestinal damage in a model of doxorubicin-induced mucositis. Doxorubicin-induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3β (GSK-3β) was assessed. Wild-type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7% of original length, and increased influx of leukocytes as compared to vehicle-injected mice (HS 1.33 ± 1.15). The protective effect of TLR-2 or TLR-9 deficiency was associated with a significant decrease of the HS as compared to WT mice. In the ileum, a minor reduction of villus length and a decreased number of infiltrating leukocytes and TUNEL-positive cells was observed. We demonstrate that the TLR-9 antagonist ODN2088 reduces doxorubicin-induced intestinal damage. Furthermore, we show that GSK-3β activity is inhibited in the absence of TLR-2. The protective capacity of GSK-3β suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR-2/GSK-3β and TLR-9 signalling pathways play a central role in the development of intestinal mucositis and we suggest a new therapeutic strategy for limiting doxorubicin-induced intestinal inflammation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.