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| Inflammation: The double-deal for NF | ||||||||||
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Exclusive to Signaling Gateway |
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NF-
B has a dual function as an initiator of systemic inflammation and as an apoptosis inhibitor in sites of injury caused by intestinal ischemia-reperfusion.
The transcription factor NF-B is activated upon infection and inflammation, but confirmation as to whether NF-B mediates inflammatory responses—or is merely a marker thereof—has been elusive. Now, Michael Karin and his colleagues have selectively deleted the catalytic subunit of IKK essential for NF-B activation, IB (IKK)-
, in intestinal epithelial cells to reveal a role of NF-B in both the inflammatory response as well as in the suppression of apoptosis.
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Previous attempts to create chemical inhibitors of NF-B have resulted in lethality due to apoptosis of the developing liver, driven by tumor necrosis factor (TNF)-
. Now, the authors have created mice with a conditional loss-of-function allele of IKK- (Ikbkb in mice). This mouse model was used to investigate the role of IKK- and NF-B in severe systemic inflammation and multiple organ dysfunction syndrome (MODS) caused by gut ischemia-reperfusion. MODS, the leading cause of death in the critically ill, can result in acute respiratory failure and acute respiratory distress syndrome, partly as a result of migratory neutrophils released from the site of reperfusion.
IKK- activation was not observed in the lungs of knockout mice subjected to gut ischemia-reperfusion. In contrast, the control mice showed NF-B DNA binding activity. The authors found that activation of IKK, NF-B and lung inflammation in response to gut ischemia-reperfusion depends on the release of the potent IKK activator TNF-. Although the ablation of IKK- from intestinal epithelial cells did not interfere with the normal development of the intestinal mucosa, it did significantly reduce neutrophil migration into the lung after gut ischemia-reperfusion, thus preventing lung edema. However, the knockout mice also demonstrated a marked increase in the number of apoptotic cells after gut ischemia-reperfusion, suggesting a role for NF-B as a protector of challenged cells and tissues from apoptosis.
These results show the dual function of the NF-B system in the initiation of systemic inflammation and in tissue protection, but also highlight that NF-B and IKK inhibitors, which could be used to treat inflammatory disorders such as MODS, must be employed with caution.
Julia Howlett, Assistant Editor
Signaling Gateway
B inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion.
Nature Medicine, 9, 575–581
(2003) 10.1038/nm849 | PubMed |
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