Opposing functions of IKKβ during acute and chronic intestinal inflammation

Lars Eckmann, Tim Nebelsiek, Alexander A. Fingerle, Sara M. Dann, Jörg Mages, Roland Lang, Sylvie Robine, Martin F. Kagnoff, Roland M. Schmid, Michael Karin, Melek C. Arkan, Florian R. Greten

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

NF-κB 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-κB-controlled responses impacts the potential utility of NF-κB inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKKβ-dependent NF-κB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-κB-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-κB-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 IKKβ in the intestinal epithelium has no impact, yet IKKβ 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-κB. Our findings caution against the therapeutic use of IKKβ/NF-κB inhibitors in acute inflammatory settings dominated by cell loss and ulceration.

Original languageEnglish (US)
Pages (from-to)15058-15063
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number39
DOIs
StatePublished - Sep 30 2008
Externally publishedYes

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Keywords

  • Apoptosis
  • Colitis
  • Heat shock protein 70
  • NF-κB
  • STAT3

ASJC Scopus subject areas

  • General

Cite this

Eckmann, L., Nebelsiek, T., Fingerle, A. A., Dann, S. M., Mages, J., Lang, R., Robine, S., Kagnoff, M. F., Schmid, R. M., Karin, M., Arkan, M. C., & Greten, F. R. (2008). Opposing functions of IKKβ during acute and chronic intestinal inflammation. Proceedings of the National Academy of Sciences of the United States of America, 105(39), 15058-15063. https://doi.org/10.1073/pnas.0808216105