| First Author | Kaczmarek A | Year | 2012 |
| Journal | J Pathol | Volume | 226 |
| Issue | 4 | Pages | 598-608 |
| PubMed ID | 21960132 | Mgi Jnum | J:181816 |
| Mgi Id | MGI:5314208 | Doi | 10.1002/path.3009 |
| Citation | Kaczmarek A, et al. (2012) Severity of doxorubicin-induced small intestinal mucositis is regulated by the TLR-2 and TLR-9 pathways. J Pathol 226(4):598-608 |
| abstractText | 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 3beta (GSK-3beta) 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-3beta activity is inhibited in the absence of TLR-2. The protective capacity of GSK-3beta suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR-2/GSK-3beta 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. |
