Abstract
Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL–1 and IL–18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL–1β (405%), IL–18 (365%), COX–2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL–18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.
Highlights
Many anti-tumor agents used to treat cancer affect rapidly dividing normal cells, including the epithelial cells of the gut, leading to various degrees of mucositis in the gastrointestinal tract [1]
Irinotecan-injected MyD88- (Fig 2A and 2B), TLR2- (Fig 2A and 2C) and TLR9(Fig 2A and 2D) knockout mice showed a partial and significant preservation of the height of the villi, conserved epithelial cell surfaces and less inflammatory infiltrates compared to the WT group treated with irinotecan (P
A semi-quantitative analysis of gut injury showed that irinotecan-injected WT mice presented a significant intestinal damage when compared to saline-administered animals, which was prevented in MyD88, TLR2- and TLR9- knockout mice (Table 2)
Summary
Many anti-tumor agents used to treat cancer affect rapidly dividing normal cells, including the epithelial cells of the gut, leading to various degrees of mucositis in the gastrointestinal tract [1]. Of particular importance in the clinical setting is the life-threatening intestinal mucositis associated with diarrhea [1]. The clinical consequences of chemotherapy-induced diarrhea include dose-reduction (45%), delays in therapy (71%) and discontinuation of therapy (3%) [1]. Loperamide, a μ2-opioid agonist agent used as a first-line treatment, and octreotide, whose mechanism is unclear and is used as a second-line treatment, are somewhat effective [1]. We demonstrated that in spite of regulating the diarrheic events, the inflammatory response associated with the mucositis induced by irinotecan is not attenuated by loperamide [5], which might explain its incomplete response in clinical setting. Other and less effective prophylactic approaches that have been suggested to manage chemotherapy-induced diarrhea include octreotide, glutamine, celecoxib, activated charcoal, absorbents, and racecadotril [6]. An improved knowledge concerning the pathogenesis of mucositis would open substantial perspectives on the adequate management of this condition
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