Constitutively active NF-kappaB triggers systemic TNFalpha-dependent inflammation and localized TNFalpha-independent inflammatory disease.
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.
Dong
Jie
J
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Jimi
Eijiro
E
Zeiss
Caroline
C
Hayden
Matthew S
MS
Ghosh
Sankar
S
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism*; D007634:Keratitis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha