title: IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice.
abstract: Intestinal damage and severe diarrhea are serious side effects of cancer chemotherapy and constrain the usage of most such therapies. Here we show that interleukin-33 (IL-33) mediates the severe intestinal mucositis in mice treated with irinotecan (CPT-11), a commonly used cancer chemotherapeutic agent. Systemic CPT-11 administration led to severe mucosal damage, diarrhea, and body weight loss concomitant with the induction of IL-33 in the small intestine (SI). This mucositis was markedly reduced in mice deficient in the IL-33R (ST2(-/-)). Moreover, recombinant IL-33 exacerbated the CPT-11-induced mucositis, whereas IL-33 blockade with anti-IL-33 antibody or soluble ST2 markedly attenuated the disease. CPT-11 treatment increased neutrophil accumulation in the SI and adhesion to mesenteric veins. Supernatants from SI explants treated with CPT-11 enhanced transmigration of neutrophils in vitro in an IL-33-, CXCL1/2-, and CXCR2-dependent manner. Importantly, IL-33 blockade reduced mucositis and enabled prolonged CPT-11 treatment of ectopic CT26 colon carcinoma, leading to a beneficial outcome of the chemotherapy. These results suggest that inhibition of the IL-33/ST2 pathway may represent a novel approach to limit mucositis and thus improve the effectiveness of chemotherapy.
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: R
authors.initials: R
authors.lastname: Guabiraba
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Besnard
authors.affiliation: Immunobiophotonics, Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: G B
authors.initials: GB
authors.lastname: Menezes
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, U1043, Institut National de la Santé et de la Recherche Médicale, Toulouse, France.
authors.forename: T
authors.initials: T
authors.lastname: Secher
authors.affiliation: 1] Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK [2] Departmet of Biotechnology, University of Technology, Baghdad, Iraq.
authors.forename: M S
authors.initials: MS
authors.lastname: Jabir
authors.affiliation: Immunobiophotonics, Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: S S
authors.initials: SS
authors.lastname: Amaral
authors.affiliation: 1] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium [2] VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Braun
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Ceará, Brazil.
authors.forename: R C P
authors.initials: RC
authors.lastname: Lima-Junior
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Ceará, Brazil.
authors.forename: R A
authors.initials: RA
authors.lastname: Ribeiro
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto (FMRP), University of São Paulo, São Paulo, Brazil.
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Immunopharmacology, Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: M M
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: 1] Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium [2] VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Graham
authors.affiliation: 1] Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK [2] CEGMR, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: F Y
authors.initials: FY
authors.lastname: Liew
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy*; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D052016:Mucositis / Q000139:chemically induced* / Q000517:prevention & control; D018123:Receptors, Interleukin / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D000077146:Irinotecan; D002166:Camptothecin