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-1β 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-1β and
IL-18 production in the ileum. asc(-/-) and casp-1(-/-) mice also had less intestinal injury and decreased IL-1β and
IL-18 production. Finally, both the absence of
IL-18 and IL-1β resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates
inflammasome activation and
inflammasome-dependent production of IL-1β and
IL-18, which mediate tissue injury during
irinotecan-induced
mucositis in mice.