Opposing functions of IKKbeta during acute and chronic intestinal inflammation.
NF-kappaB 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-kappaB-controlled responses impacts the potential utility of NF-kappaB inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKKbeta-dependent NF-kappaB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-kappaB-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-kappaB-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 IKKbeta in the intestinal epithelium has no impact, yet IKKbeta 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-kappaB. Our findings caution against the therapeutic use of IKKbeta/NF-kappaB inhibitors in acute inflammatory settings dominated by cell loss and ulceration.
Eckmann
Lars
L
Department of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. leckmann@ucsd.edu
Nebelsiek
Tim
T
Fingerle
Alexander A
AA
Dann
Sara M
SM
Mages
Jörg
J
Lang
Roland
R
Robine
Sylvie
S
Kagnoff
Martin F
MF
Schmid
Roland M
RM
Karin
Michael
M
Arkan
Melek C
MC
Greten
Florian R
FR
D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D015870:Gene Expression; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics; D007413:Intestinal Mucosa; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D007375:Interleukin-1; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016264:Dextran Sulfate; D051550:I-kappa B Kinase