title: A role for NF-kappa B subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock.
abstract: To evaluate the possibility that NF-kappaB subunits p50 and p65 have a role in limiting the systemic inflammatory response induced by endotoxin, we compared the susceptibility of wild-type (WT), p65+/-, p50-/-, and p50-/-p65+/- (3X) mice to LPS-induced shock. Interestingly, whereas p65+/- mice were no more sensitive than WT mice to LPS-induced shock, 3X mice were exquisitely sensitive to the toxic effects of LPS. Mice lacking p50 alone displayed an intermediate phenotype. Sensitivity to LPS was a property of the innate immune system and was characterized by elevated circulating levels of TNF in both p50-/- and 3X mice. The ability of LPS to induce shock depended upon TNF, and 3X mice were significantly more sensitive to the toxic effects of TNF than were p50-deficient mice. The expression of several LPS-inducible proinflammatory genes, including IFN-gamma, was significantly higher within the spleens of p50-/- mice than in the spleens of WT mice, and interestingly, the expression of IFN-gamma was augmented still further within the spleens of 3X mice. These results demonstrate that NF-kappaB subunits p50 and p65 have critical inhibitory functions during the systemic response to LPS and raise the possibility that these functions could be essential in preventing mortality associated with systemic inflammatory response syndromes.
authors.affiliation: Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gadjeva
authors.forename: Michal F
authors.initials: MF
authors.lastname: Tomczak
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Yan Yan
authors.initials: YY
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Dull
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Susan E
authors.initials: SE
authors.lastname: Erdman
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Michael
authors.initials: M
authors.lastname: Carroll
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000098:blood supply / Q000276:immunology; D004487:Edema / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008168:Lung / Q000098:blood supply / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha