ROS, Hsp27, and IKKβ mediate dextran sodium sulfate (DSS) activation of IκBa, NFκB, and IL-8
Article first published online: 11 DEC 2008
Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 15, Issue 5, pages 673–683, May 2009
How to Cite
Bhattacharyya, S., Dudeja, P. K. and Tobacman, J. K. (2009), ROS, Hsp27, and IKKβ mediate dextran sodium sulfate (DSS) activation of IκBa, NFκB, and IL-8. Inflamm Bowel Dis, 15: 673–683. doi: 10.1002/ibd.20821
- Issue published online: 7 APR 2009
- Article first published online: 11 DEC 2008
- Manuscript Accepted: 14 OCT 2008
- Manuscript Received: 23 SEP 2008
- Department of Veterans Affairs
- NIDDK. Grant Numbers: DK54016, DK68324
- reactive oxygen species (ROS);
- sulfated polysaccharide;
- IKK signalosome;
- innate immunity;
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-IκBα, nuclear NFκB (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 NFκB-IL-8 activation.
Results: DSS-induced increases were inhibited by the ROS scavengers Tempol and Tiron, were associated with decreased phosphorylation of MAPK12 (p38γ), MAPK 13 (p38δ), and Hsp27, and required the IκB kinase (IKK) signalosome component IKKβ. 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 IκBα, NFκB, and IL-8 through an ROS-Hsp27-IKKβ-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.
(Inflamm Bowel Dis 2008)