Inhibition of IKK and NF-κB Prevents Inflammation but Increases Local Injury

Michael Karin, Ph.D.
University of California San Diego
P42ES10337

Background: NFκB is a transcription factor that is a major regulator of immune responses stimulated by pro-inflammatory agents such as tumor necrosis factor, viruses, interleukin-1, and bacteria. NFκB normally resides in the cytoplasm bound by an inhibitory protein known as IκB. Phosphorylation of IκB by IκB kinase-β (IKK-β) releases NFκB, which then moves into the nucleus where it acts in the induction of numerous regulatory genes of the immune system. The products of these genes are pro-inflammatory factors.

This paper describes the role of NFκB 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. Since activated nuclear NFκB is often found at sites of inflammation and infection, it is thought to be a key mediator of both acute and chronic inflammatory diseases such as septic shock and asthma. 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. NFκB has been proposed as an important contributor in amplifying this response, but it is unclear whether it is crucial for initiating the inflammatory response.

Advance: 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, these investigators determined that mice whose intestinal cells lacked IKK-β did not produce the predicted systemic inflammatory response. IKK-β works as a complex with two other proteins to allow activation of NFκB following infection. However, the lack of IKK-β caused severe damage to the reperfused intestinal mucosa in these mice because of apoptosis or programmed cell death. Therefore, therapeutically blocking the activity of IKK-β in humans would likely block the inflammatory response, preventing MODS. However, this would occur at the cost of severe tissue injury caused by programmed cell death. These results show the dual roles for the NFκB system in both tissue protection and systemic inflammation.

Implication: This paper identifies two points that are important regarding future development and possible therapeutic use of IKK and NFκB inhibitors as anti-inflammatory agents. First, it provides "unequivocal and direct proof that NFκB is not just a marker of inflammation, but is the driving force for initiation and spread of acute and systemic inflammation." Second is "a primary role for NFκB activation in response to physical and chemical stressors is to protect the challenged cells or tissues from apoptosis." Although IKK-β and NFκB 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.

Citation: Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med. 2003 Apr 7.