| Author |
Arifa, Raquel D. N. Madeira, Mila F. M. de Paula, Talles P. Lima, Renata L. Tavares, Livia D. Menezes-Garcia, Zélia Fagundes, Caio T. Rachid, Milene A. Ryffel, Bernhard Zamboni, Dario S. Teixeira, Mauro M. Souza, Danielle G. |
| Description |
Author Affiliation: Arifa RD ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); Madeira MF ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); de Paula TP ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); Lima RL ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); Tavares LD ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); Menezes-Garcia Z ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); Fagundes CT ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil); Rachid MA ( Laboratory of Apoptosis, Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.); Ryffel B ( INEM-UMR7355, Molecular Immunology, University and National Center for Scientific Research, Orleans, France.); Zamboni DS ( Department of Cell and Molecular Biology, and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo (FMRP/USP), Ribeirão Preto, Brazil.); Teixeira MM ( Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.); Souza DG ( Laboratory of Microorganism-Host Interaction, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil) |
| Abstract |
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-1ß 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-1ß and IL-18 production in the ileum. asc(-/-) and casp-1(-/-) mice also had less intestinal injury and decreased IL-1ß and IL-18 production. Finally, both the absence of IL-18 and IL-1ß resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates inflammasome activation and inflammasome-dependent production of IL-1ß and IL-18, which mediate tissue injury during irinotecan-induced mucositis in mice. |
