Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 39, Pages 15058-15063Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0808216105
Keywords
NF-kappa B; colitis; STAT3; apoptosis; Heat shock protein 70
Categories
Funding
- National Institutes of Health [DK70867, DK35108, RR17030]
- University of California at San Diego Digestive Diseases Research Development Center [DK80506]
- American Association for Cancer Research
- Wilhelm Sander-Stiftung [2005.146.1]
- Deutsche Forschungsgemeinschaft (Emmy-Noether-Program [Gr1916/2-2, SFB 456]
- Deutsche Krebshilfe [106772]
- Fritz-Thyssen-Stiftung [10.05.2.168]
- American Cancer Society Research
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NF-kappa B is a key transcriptional regulator of inflammatory responses, but also controls expression of prosurvival genes, whose products protect tissues from damage and may thus act indirectly in an antiinflammatory fashion. The variable importance of these two distinct NF-kappa B-controlled responses impacts the potential utility of NF-kappa B inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKK beta-dependent NF-kappa B activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-kappa B-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-kappa B-dependent recruitment of inflammatory cells that secrete cytoprotective factors. In contrast, in IL-10-deficient mice, which serve as a model of chronic T cell-dependent colitis, ablation of IKK beta in the intestinal epithelium has no impact, yet IKK beta deficiency in myeloid cells attenuates inflammation and prolongs survival. These results highlight the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-kappa B. Our findings caution against the therapeutic use of IKK beta/NF-kappa B inhibitors in acute inflammatory settings dominated by cell loss and ulceration.
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