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 +11 more
TLDR
In murine models, inhibition of IKKβ-dependent NF-κB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract, highlighting the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-σκB.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.read more
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References
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Journal ArticleDOI
Interleukin-10-deficient mice develop chronic enterocolitis
TL;DR: The results indicate that the bowel inflammation in the mutants originates from uncontrolled immune responses stimulated by enteric antigens and that IL-10 is an essential immunoregulator in the intestinal tract.
Journal ArticleDOI
Signaling to NF-kappaB.
Matthew S. Hayden,Sankar Ghosh +1 more
TL;DR: An overview of established NF-kappaB signaling pathways is provided with focus on the current state of research into the mechanisms that regulate IKK activation and NF- kappaB transcriptional activity.
Journal ArticleDOI
NF-kappaB: linking inflammation and immunity to cancer development and progression.
Michael Karin,Florian R. Greten +1 more
TL;DR: The hypothesis is put forward that activation of nuclear factor-κB by the classical, IKK-β (inhibitor-of-NF-β kinase-β)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
Journal ArticleDOI
NF-κB at the crossroads of life and death
Michael Karin,Anning Lin +1 more
TL;DR: The choice between life and death is one of the major events in regulation of the immune system and a major regulator of such life or death decisions is the transcription factor NF-κB as mentioned in this paper.
Journal ArticleDOI
IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
Florian R. Greten,Lars Eckmann,Tim F. Greten,Jin Mo Park,Zhi-Wei Li,Laurence J. Egan,Laurence J. Egan,Martin F. Kagnoff,Michael Karin +8 more
TL;DR: It is shown that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size, which is linked to increased epithelial apoptosis during tumor promotion.