Constitutively active NF-κB triggers systemic TNFα-dependent inflammation and localized TNFα-independent inflammatory disease

NF-kappa B is well established as a key component of the inflammatory response. However, the precise mechanisms through which NF-kappa B activation contributes to inflammatory disease states remain poorly defined. To test the role of NF-kappa B in inflammation, we created a knock-in mouse that expresses a constitutively active form of NF-kappa B 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 TNFa, IL-1 beta,and MMP-9, similar to that seen in human keratoconjunctivitis sicca (KCS) or "dry eyes." Therefore, our results show that, while constitutively active NF-kappa B 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-kappa B, but are independent of TNFR1 signaling.