title: The flavonoid luteolin worsens chemical-induced colitis in NF-kappaB(EGFP) transgenic mice through blockade of NF-kappaB-dependent protective molecules.
abstract: BACKGROUND
  The flavonoid luteolin has anti-inflammatory properties both in vivo and in vitro. However, the impact of luteolin on experimental models of colitis is unknown.
  
  
  RESULTS
  To address the therapeutic impact of luteolin, NF-kappaB(EGFP) transgenic mice were fed a chow diet containing 2% luteolin- or isoflavone-free control chow (AIN-76), and acute colitis was induced using 3% dextran sodium sulfate (DSS). Additionally, development of spontaneous colitis was evaluated in IL-10(-/-);NF-kappaB(EGFP) transgenic mice fed 2% luteolin chow diet or control chow diet. Interestingly, NF-kappaB(EGFP) transgenic mice exposed to luteolin showed worse DSS-induced colitis (weight loss, histological scores) compared to control-fed mice, whereas spontaneous colitis in IL-10(-/-);NF-kappaB(EGFP) mice was significantly attenuated. Macroscopic imaging of live resected colon showed enhanced EGFP expression (NF-kappaB activity) in luteolin-fed mice as compared to control-fed animals after DSS exposure, while cecal EGFP expression was attenuated in luteolin-fed IL-10(-/-) mice. Interestingly, confocal microscopy showed that EGFP positive cells were mostly located in the lamina propria and not in the epithelium. Caspase 3 activation was significantly enhanced whereas COX-2 gene expression was reduced in luteolin-fed, DSS-exposed NF-kappaB(EGFP) transgenic mice as assessed by Western blot and immunohistochemical analysis. In vitro, luteolin sensitized colonic epithelial HT29 cells to TNFalpha-induced apoptosis, caspase 3 activation, DNA fragmentation and reduced TNFalpha-induced C-IAP1, C-IAP2 and COX-2 gene expression.
  
  
  CONCLUSIONS
  We conclude that while luteolin shows beneficial effects on spontaneous colitis, it aggravates DSS-induced experimental colitis by blocking NF-kappaB-dependent protective molecules in enterocytes.
authors.affiliation: Department of Medicine and Center for GI Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karrasch
authors.forename: Joo-Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Byung Ik
authors.initials: BI
authors.lastname: Jang
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
mesh_terms: D000256:Adenoviridae / Q000201:enzymology; D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D019073:HT29 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency*; D008156:Luciferases / Q000235:genetics; D047311:Luteolin / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D016328:NF-kappa B; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D004815:Epidermal Growth Factor; D012313:RNA; D008156:Luciferases; D020169:Caspases; D015232:Dinoprostone; D047311:Luteolin