The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion.
We studied the role of NF-kappaB in acute inflammation caused by gut ischemia-reperfusion through selective ablation of IkappaB kinase (IKK)-beta, the catalytic subunit of IKK that is essential for NF-kappaB activation. Ablation of IKK-beta in enterocytes prevented the systemic inflammatory response, which culminates in multiple organ dysfunction syndrome (MODS) that is normally triggered by gut ischemia-reperfusion. IKK-beta removal from enterocytes, however, also resulted in severe apoptotic damage to the reperfused intestinal mucosa. These results show the dual function of the NF-kappaB system, which is responsible for both tissue protection and systemic inflammation, and underscore the caution that should be exerted in using NF-kappaB and IKK inhibitors.
Chen
Lee-Wei
LW
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, California, USA.
Egan
Laurence
L
Li
Zhi-Wei
ZW
Greten
Florian R
FR
Kagnoff
Martin F
MF
Karin
Michael
M
D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D007249:Inflammation / Q000517:prevention & control*; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000517:prevention & control; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse