title: The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis.
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.
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil; Laboratory of Molecular Biology, Department of Pathology, Cancer Institute of Ceará, Fortaleza, Brazil.
authors.forename: Deysi V T
authors.initials: DV
authors.lastname: Wong
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Roberto C P
authors.initials: RC
authors.lastname: Lima-Júnior
authors.affiliation: Department of Pathology and Forensic Medicine, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Cibele B M
authors.initials: CB
authors.lastname: Carvalho
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Borges
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Carlos W S
authors.initials: CW
authors.lastname: Wanderley
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Amanda X C
authors.initials: AX
authors.lastname: Bem
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Caio A V G
authors.initials: CA
authors.lastname: Leite
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Maraiza A
authors.initials: MA
authors.lastname: Teixeira
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Gabriela L P
authors.initials: GL
authors.lastname: Batista
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Rangel L
authors.initials: RL
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Morphology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Gerly A C
authors.initials: GA
authors.lastname: Brito
authors.affiliation: Department of Pathology and Forensic Medicine, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Paulo R C
authors.initials: PR
authors.lastname: Almeida
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Nucleus for the Study of Toxicities of the Cancer Treatment, Department of Physiology and Pharmacology, Faculty of Medicine-Federal University of Ceará, Fortaleza, Brazil; Department of Clinical Oncology, Cancer Institute of Ceará, Fortaleza, Brazil.
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007410:Intestinal Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D000077146:Irinotecan; D051379:Mice; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D000077146:Irinotecan; D009195:Peroxidase; D002166:Camptothecin