Constitutive intestinal NF-?B does not trigger destructive inflammation unless accompanied by MAPK activation.

ABSTRACT: Nuclear factor (NF)-?B, activated by I?B kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-?B and one of its main activators and transcriptional targets, tumor necrosis factor (TNF), are up-regulated in many inflammatory diseases that are accompanied by tissue destruction. The etiology of many inflammatory diseases is poorly understood, but often depends on genetic factors and environmental triggers that affect NF-?B and related pathways. It is unknown, however, whether persistent NF-?B activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKK?(EE)(IEC) mice, which express a constitutively active form of IKK? in intestinal epithelial cell (IECs). IKK?(EE)(IEC) mice exhibit NF-?B activation in IECs and express copious amounts of inflammatory chemokines, but only small amounts of TNF. Although IKK?(EE)(IEC) mice exhibit inflammatory cell infiltration in the lamina propria (LP) of their small intestine, they do not manifest tissue damage. Yet, upon challenge with relatively mild immune and microbial stimuli, IKK?(EE)(IEC) mice succumb to destructive acute inflammation accompanied by enterocyte apoptosis, intestinal barrier disruption, and bacterial translocation. Inflammation is driven by massive TNF production, which requires additional activation of p38 and extracellular-signal-regulated kinase mitogen-activated protein kinases (MAPKs).

SUBMITTER: Guma M 

PROVIDER: S-EPMC3171091 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature