| First Author | Dong J | Year | 2010 |
| Journal | Genes Dev | Volume | 24 |
| Issue | 16 | Pages | 1709-17 |
| PubMed ID | 20713516 | Mgi Jnum | J:163663 |
| Mgi Id | MGI:4829406 | Doi | 10.1101/gad.1958410 |
| Citation | Dong J, et al. (2010) Constitutively active NF-kappaB triggers systemic TNFalpha-dependent inflammation and localized TNFalpha-independent inflammatory disease. Genes Dev 24(16):1709-17 |
| abstractText | NF-kappaB is well established as a key component of the inflammatory response. However, the precise mechanisms through which NF-kappaB activation contributes to inflammatory disease states remain poorly defined. To test the role of NF-kappaB in inflammation, we created a knock-in mouse that expresses a constitutively active form of NF-kappaB 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 TNFalpha, IL-1beta, and MMP-9, similar to that seen in human keratoconjunctivitis sicca (KCS) or 'dry eyes.' Therefore, our results show that, while constitutively active NF-kappaB 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-kappaB, but are independent of TNFR1 signaling. |
