title: Rutin has intestinal antiinflammatory effects in the CD4+ CD62L+ T cell transfer model of colitis.
abstract: Rutin, one of the most abundant flavonoids in nature, has been shown to exert intestinal antiinflammatory effects in experimental models of colitis. Our aim was to study the antiinflamatory effect of rutin in the CD4+ CD62L+ T cell transfer model of colitis, one of the closest to the human disease. Colitis was induced by transfer of CD4+ CD62L+ T cells to Rag1(-/-) mice. Rutin was administered by gavage as a postreatment. Treatment with rutin improved colitis at the dose of 57mg/kg/day, while no effect was noted with 28.5mg/kg/day. Therapeutic benefit was evidenced by a reduced disease activity index, weight loss and damage score, plus a 36% lower colonic myeloperoxidase and a 54% lower alkaline phosphatase activity. In addition, a decreased secretion of proinflammatory cytokines (IFNγ and TNFα) by mesenteric lymph node cells was observed ex vivo. The colonic expression of proinflammatory genes, including IFNγ, TNFα, CXCL1, S100A8 and IL-1β, was significantly reduced by more than 80% with rutin as assessed by RT-qPCR. Flavonoid treated mice exhibited decreased activation of splenic CD4+ cells (STAT4 phosphorylation and IFNγ expression) and reduced plasma cytokine levels. This effect was also apparent in mucosal lymphocytes based on reduced STAT4 phosphorylation. The protective effect was comparable to that of 3mg/kg/day budesonide. Rutin had no effect on splenocytes or murine T cells in vitro, while its aglycone, quercetin, exhibited a concentration dependent inhibition of proinflammatory cytokines, including IFNγ. Rutin but not quercetin showed vectorial basolateral to apical transport in IEC18 cells, associated with reduced biotransformation. We conclude that rutin exerts intestinal antiinflammatory activity in chronic, T lymphocyte dependent colitis via quercetin release and actions involving mucosal and lymph node T cells. Our results suggest that rutin may be useful in the management of inflammatory bowel disease in appropriate dosage conditions.
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: cristimascaraque@gmail.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mascaraque
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: cjarandaclemente@gmail.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Aranda
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: boryus13@hotmail.com.
authors.forename: Borja
authors.initials: B
authors.lastname: Ocón
authors.affiliation: Department of Physiology and Pharmacology, HEVEFARM, IBSAL, CIBERehd, University of Salamanca, Spain. Electronic address: mjmonte@usal.es.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Monte
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: msuarez@ugr.es.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Suárez
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: zarzuelo@ugr.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.affiliation: Department of Physiology and Pharmacology, HEVEFARM, IBSAL, CIBERehd, University of Salamanca, Spain. Electronic address: jjgmarin@usal.es.
authors.forename: José Juan García
authors.initials: JJ
authors.lastname: Marín
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: omartine@ugr.es.
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Augustin
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: fsanchez@ugr.es.
authors.forename: Fermín Sánchez
authors.initials: FS
authors.lastname: de Medina
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D003092:Colitis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D007420:Intestine, Large / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D012431:Rutin / Q000494:pharmacology / Q000627:therapeutic use*; D050797:STAT4 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018398:Homeodomain Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; C064658:RAG-1 protein; D012431:Rutin; D011794:Quercetin; D009195:Peroxidase; D000469:Alkaline Phosphatase
keywords: CD4+ CD62L+ T cell transfer colitis; Epithelial transport; Flavonoid; Rutin