| Author |
Mascaraque, Cristina Aranda, Carlos Ocón, Borja Monte, María Jesús Suárez, María Dolores Zarzuelo, Antonio Marín, José Juan García Martínez-Augustin, Olga de Medina, Fermín Sánchez |
| Description |
Author Affiliation: Mascaraque C ( Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: cristimascaraque@gmail.com.); Aranda C ( 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.); Ocón B ( Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: boryus13@hotmail.com.); Monte MJ ( Department of Physiology and Pharmacology, HEVEFARM, IBSAL, CIBERehd, University of Salamanca, Spain. Electronic address: mjmonte@usal.es.); Suárez MD ( 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.); Zarzuelo A ( Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: zarzuelo@ugr.es.); Marín JJ ( Department of Physiology and Pharmacology, HEVEFARM, IBSAL, CIBERehd, University of Salamanca, Spain. Electronic address: jjgmarin@usal.es.); Martínez-Augustin O ( 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.); de Medina FS ( Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. Electronic address: fsanchez@ugr.es.) |
| 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 TNF ) by mesenteric lymph node cells was observed ex vivo. The colonic expression of proinflammatory genes, including IFNγ, TNF , CXCL1, S100A8 and IL-1ß, 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. |
| Subject Keyword |
Discipline Pharmacology Anti-inflammatory Agents Therapeutic Use Colitis Drug Therapy Rutin Alkaline Phosphatase Metabolism Animals Pharmacology Cell Line Cells, Cultured Blood Pathology Cytokines Genetics Disease Models, Animal Female Homeodomain Proteins Intestine, Large Drug Effects Lymph Nodes Cytology Mice, Inbred C57bl Mice, Knockout Nf-kappa B Peroxidase Quercetin Rna, Messenger Rats, Wistar Stat4 Transcription Factor Spleen T-lymphocytes Journal Article Research Support, Non-u.s. Gov't |
