title: Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation.
abstract: Nuclear factor (NF)-κB, activated by IκB kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-κB 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-κB and related pathways. It is unknown, however, whether persistent NF-κB activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKKβ(EE)(IEC) mice, which express a constitutively active form of IKKβ in intestinal epithelial cell (IECs). IKKβ(EE)(IEC) mice exhibit NF-κB activation in IECs and express copious amounts of inflammatory chemokines, but only small amounts of TNF. Although IKKβ(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, IKKβ(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).
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.forename: Dariusz
authors.initials: D
authors.lastname: Stepniak
authors.forename: Helena
authors.initials: H
authors.lastname: Shaked
authors.forename: Martina E
authors.initials: ME
authors.lastname: Spehlmann
authors.forename: Steve
authors.initials: S
authors.lastname: Shenouda
authors.forename: Hilde
authors.initials: H
authors.lastname: Cheroutre
authors.forename: Ildelfonso
authors.initials: I
authors.lastname: Vicente-Suarez
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kagnoff
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051550:I-kappa B Kinase; D020929:Mitogen-Activated Protein Kinase Kinases