Opposing functions of IKKβ during acute and chronic intestinal inflammation

• DOI: 10.1073/pnas.0808216105
• Publication Date: 2008-09-25T01:07:01Z
• Authors: Lars Eckmann; Tim Nebelsiek; Alexander A. Fing...; Sara M. Dann; Jörg Mages; Roland Lang; Sylvie Robine; Martin F. Kagnoff; Roland M. Schmid; Michael Karin; Melek C. Arkan; Florian R. Greten
• Keywords: Proinflammatory cytokine; Intestinal epithelium

NF-κB is a key transcriptional regulator of inflammatory responses, but also controls expression prosurvival genes, whose products protect tissues from damage and may thus act indirectly in an antiinflammatory fashion. The variable importance these two distinct NF-κB-controlled responses impacts the potential utility inhibition as treatment strategy for intractable conditions, such bowel disease. Here, we show murine models that IKKβ-dependent activation exacerbates acute inflammation, attenuates chronic disease intestinal tract. Acute ulcerating inflammation aggravated because diminished NF-κB-mediated protection against epithelial cell apoptosis delayed mucosal regeneration secondary to reduced NF-κB-dependent recruitment cells secrete cytoprotective factors. In contrast, IL-10-deficient mice, which serve model T cell-dependent colitis, ablation IKKβ epithelium has no impact, yet deficiency myeloid prolongs survival. These results highlight striking context tissue dependence proinflammatory antiapoptotic functions NF-κB. Our findings caution therapeutic use IKKβ/NF-κB inhibitors settings dominated by loss ulceration.