The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion

Nat Med. 2003 May;9(5):575-81. doi: 10.1038/nm849. Epub 2003 Apr 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Gene Expression Regulation
  • I-kappa B Kinase
  • Inflammation / prevention & control*
  • Intestines / blood supply*
  • Ischemia / complications*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Multiple Organ Failure / prevention & control
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology*
  • Reperfusion Injury / prevention & control*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse