Inhibiting IKK-[beta] and NF-[kappa]B prevents systemic inflammation but increases local injury.

Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M. 2003. The two faces of IKK and NF-[kappa]B inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 9:575-581.

The transcription factor NF-[kappa]B is a major regulator of immune responses stimulated by proinflammatory stimuli such as tumor necrosis factor, viral and bacterial infections, and chemical and physical stressors. Because NF-[kappa]B is detected at sites of inflammation and infection, it is thought to play a role in acute and chronic inflammatory disorders such as septic shock and asthma. NF-[kappa]B normally resides in the cytoplasm bound by an inhibitory protein known as I[kappa]B. Phosphorylation of I[kappa]B by I[kappa]B kinase (IKK)-[beta] releases NF-[kappa]B, which then moves into the nucleus. There, it acts in the induction of numerous regulatory genes of the immune system. The products of these genes are proinflammatory factors.

NIEHS grantee Michael Karin of the University of San Diego, California, and colleagues sought to elucidate the role of NF-[kappa]B in severe systemic inflammation and multiple organ dysfunction syndrome (MODS). MODS, a serious and often fatal condition, occurs in patients with septic and toxic shock and other systemic inflammatory response syndromes. In MODS, activated neutrophils infiltrate tissues, resulting in the release of proteases, reactive oxygen species, and various cytokines and inflammatory mediators that contribute to tissue injury and failure. NF-[kappa]B has been proposed as an important amplifier of this response, but it is unclear whether it is crucial for initiating the inflammatory response.

Using a classic model to induce severe inflammation called gut ischemia-reperfusion, in which the blood supply is cut off to the gastrointestinal tract for 30 minutes and then restored, the team determined that mice whose intestinal cells lacked IKK-[beta] did not have the predicted systemic inflammatory response. However, the lack of IKK-[beta] caused severe damage to the reperfused intestinal mucosa in these mice because of apoptosis. Therefore, the authors postulate that therapeutically blocking the activity of IKK-[beta] in humans would likely block the inflammatory response, preventing MODS. However, this would occur at the cost of severe tissue injury. These results show the dual roles for the NF-[kappa]B system in both tissue protection and systemic inflammation.

The authors assert that this study provides unequivocal and direct proof that NF-[kappa]B is not just a marker of inflammation, but is the driving force for initiation and spread of acute and systemic inflammation. And they point to a primary role for NF-[kappa]B activation in response to physical and chemical stressors in protecting the challenged cells or tissues from apoptosis. Although IKK-[beta] and NF-[kappa]B inhibitors are likely to be potent anti-inflammatory agents, this study underscores the potential danger of using them during severe inflammatory episodes caused by shock, trauma, and other critical illnesses.