title: ROS, Hsp27, and IKKbeta mediate dextran sodium sulfate (DSS) activation of IkappaBa, NFkappaB, and IL-8.
abstract: BACKGROUND
  Dextran sodium sulfate (DSS) is a sulfated polysaccharide that has been very widely used to induce inflammation in experimental models of inflammatory bowel disease in which the effects of pharmacologic and biologic therapies are tested. However, the precise mechanisms by which DSS induces inflammation have not been elucidated.
  
  
  METHODS
  DSS-induced increases in phospho-IkappaBalpha, nuclear NFkappaB (p65), and IL-8 secretion in human colonic epithelial cells in tissue culture are attributable to a reactive oxygen species (ROS)-induced pathway of inflammation, and do not require TLR4, MyD88, or Bcl10, which are associated with the innate immune pathway of NFkappaB-IL-8 activation.
  
  
  RESULTS
  DSS-induced increases were inhibited by the ROS scavengers Tempol and Tiron, were associated with decreased phosphorylation of MAPK12 (p38gamma), MAPK 13 (p38delta), and Hsp27, and required the IkappaB kinase (IKK) signalosome component IKKbeta. In ex vivo colonic tissue from TLR4-deficient mice, or following knockdown of MyD88 or Bcl10 or exposure to an IRAK 1/4 inhibitor, DSS effects were not suppressed. Data demonstrated that DSS activates IkappaBalpha, NFkappaB, and IL-8 through an ROS-Hsp27-IKKbeta-mediated pathway, and not through an innate immune cascade.
  
  
  CONCLUSIONS
  These results suggest that DSS models of inflammation may not be optimal for evaluation of interventions that involve mechanisms of innate immunity.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Tobacman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism* / Q000502:physiology; D020672:I-kappa B Proteins / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; C507779:MYD88 protein, human; D018832:Molecular Chaperones; D053594:Myeloid Differentiation Factor 88; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D016264:Dextran Sulfate; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase; C496560:IKBKB protein, human