| First Author | Arifa RD | Year | 2014 |
| Journal | Am J Pathol | Volume | 184 |
| Issue | 7 | Pages | 2023-34 |
| PubMed ID | 24952429 | Mgi Jnum | J:213866 |
| Mgi Id | MGI:5586762 | Doi | 10.1016/j.ajpath.2014.03.012 |
| Citation | Arifa RD, et al. (2014) Inflammasome activation is reactive oxygen species dependent and mediates irinotecan-induced mucositis through IL-1beta and IL-18 in mice. Am J Pathol 184(7):2023-34 |
| abstractText | Irinotecan is a useful chemotherapeutic for the treatment of various cancers. Irinotecan treatment is associated with mucositis, which clearly limits the use of the drug. Mechanisms that account for mucositis are only partially known. This study assessed mechanisms and the role of inflammasome activation in irinotecan-induced mucositis. Mucositis in mice was induced by irinotecan injection in C57BL/6 wild-type, gp91phox(-/-), il-18(-/-), casp-1(-/-), and asc(-/-) mice once a day for 4 consecutive days. In some experiments, mice received apocynin to inhibit NADPH oxidase (NOX), IL-1 receptor antagonist, or IL-18 binding protein to prevent activation of IL-1 and IL-18 receptors, respectively. Mice were euthanized 7 days after the beginning of irinotecan treatment, and small intestines were collected for analysis. Irinotecan treatment resulted in increased IL-1beta and IL-18 production in ileum and NOX-2-dependent oxidative stress. gp91phox(-/-) and apocynin-treated mice had diminished oxidative stress and less severe mucositis. Furthermore, treatment with apocynin decreased caspase-1 activation and IL-1beta and IL-18 production in the ileum. asc(-/-) and casp-1(-/-) mice also had less intestinal injury and decreased IL-1beta and IL-18 production. Finally, both the absence of IL-18 and IL-1beta resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates inflammasome activation and inflammasome-dependent production of IL-1beta and IL-18, which mediate tissue injury during irinotecan-induced mucositis in mice. |
