title: Targeted inhibition of IL-18 attenuates irinotecan-induced intestinal mucositis in mice.
abstract: OBJECTIVE
  Intestinal mucositis is a common side-effect of irinotecan-based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL-18 is up-regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the role of IL-18 in the pathogenesis of irinotecan-induced intestinal mucositis.
  
  
  METHODS
  Wild type (WT), IL-18 or caspase-1 knockout mice were treated with either saline or irinotecan (60 mg·kg⁻¹ per 4 days, i.p.) or the IL-18 binding protein (IL-18bp, 10 mg·kg⁻¹) before irinotecan. On day 5, diarrhoea was monitored and proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible NOS (iNOS) activity, and detection of IL-18 expression.
  
  
  RESULTS
  Irinotecan induced severe diarrhoea accompanied by intestinal injury (villi shortening and increased crypt depth). Additionally, irinotecan treatment increased MPO and iNOS activity, iNOS immunostaining and IL-18 expression in WT mice compared with saline treatment. The IL-18 production was associated with macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to ACh after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhoea were prevented in caspase-1 knockout and IL-18 knockout mice, and in IL-18bp-treated WT mice. Furthermore, the Survival of irinotecan-treated mice was increased and iNOS immunoexpression and IL-18 production prevented in IL-18 knockout mice.
  
  
  CONCLUSIONS
  Targeting IL-18 function may be a promising therapeutic approach to decreasing the severity of intestinal mucositis during irinotecan treatment regimens.
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: R C P
authors.initials: RC
authors.lastname: Lima-Júnior
authors.forename: H C
authors.initials: HC
authors.lastname: Freitas
authors.forename: D V T
authors.initials: DV
authors.lastname: Wong
authors.forename: C W S
authors.initials: CW
authors.lastname: Wanderley
authors.forename: L G
authors.initials: LG
authors.lastname: Nunes
authors.forename: L L
authors.initials: LL
authors.lastname: Leite
authors.forename: S P
authors.initials: SP
authors.lastname: Miranda
authors.forename: M H L P
authors.initials: MH
authors.lastname: Souza
authors.forename: G A C
authors.initials: GA
authors.lastname: Brito
authors.forename: P J C
authors.initials: PJ
authors.lastname: Magalhães
authors.forename: M M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: R A
authors.initials: RA
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D016503:Drug Delivery Systems / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052016:Mucositis / Q000188:drug therapy* / Q000378:metabolism; D009924:Organ Culture Techniques
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein; D000077146:Irinotecan; D002166:Camptothecin
keywords: IL-18; IL-18 binding protein; cancer chemotherapy toxicity; gut; inflammation; irinotecan; mucositis