ROS, Hsp27, and IKKβ mediate dextran sodium sulfate (DSS) activation of IκBa, NFκB, and IL-8
✍ Scribed by Sumit Bhattacharyya; Pradeep K. Dudeja; Joanne K. Tobacman
- Book ID
- 102267916
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 392 KB
- Volume
- 15
- Category
- Article
- ISSN
- 1078-0998
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✦ Synopsis
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-IB␣, nuclear NFB (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 NFB-IL-8 activation.
Results: DSS-induced increases were inhibited by the ROS scavengers Tempol and Tiron, were associated with decreased phosphorylation of MAPK12 (p38␥), MAPK 13 (p38␦), and Hsp27, and required the IB kinase (IKK) signalosome component IKK. 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 IB␣, NFB, and IL-8 through an ROS-Hsp27-IKK-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.