Constitutively active NF-κB triggers systemic TNFα-dependent inflammation and localized TNFα-independent inflammatory disease
- 1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 2Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 3Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 4Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
Abstract
NF-κB is well established as a key component of the inflammatory response. However, the precise mechanisms through which NF-κB activation contributes to inflammatory disease states remain poorly defined. To test the role of NF-κB in inflammation, we created a knock-in mouse that expresses a constitutively active form of NF-κB p65 dimers. These mice are born at normal Mendelian ratios, but display a progressive, systemic hyperinflammatory condition that results in severe runting and, typically, death 8–20 d after birth. Examination of homozygous knock-in mice demonstrates significant increases in proinflammatory cytokines and chemokines. Remarkably, crossing this strain with mice lacking TNF receptor 1 (TNFR1) leads to a complete rescue of the hyperinflammatory phenotype. However, upon aging, these rescued mice begin to display chronic keratitis accompanied by increased corneal expression of TNFα, IL-1β, and MMP-9, similar to that seen in human keratoconjunctivitis sicca (KCS) or “dry eyes.” Therefore, our results show that, while constitutively active NF-κB can trigger systemic inflammation, it does so indirectly, through increased TNF production. However, certain inflammatory disease states, such as keratitis or KCS, a condition that is seen in Sjogren's syndrome, are dependent on NF-κB, but are independent of TNFR1 signaling.
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Footnotes
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↵6 Corresponding author.
E-MAIL sg2715{at}columbia.edu; FAX (212) 342-1290.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1958410.
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Supplemental material is available at http://www.genesdev.org.
- Received June 9, 2010.
- Accepted July 6, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press