title: Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-kappa B in leukocyte recruitment.
abstract: NF-kappaB binding sites are present in the promoter regions of many acute phase and inflammatory response genes, suggesting that NF-kappaB plays an important role in the initiation of innate immune responses. However, targeted mutations of the various NF-kappaB family members have yet to identify members responsible for this critical role. RelA-deficient mice die on embryonic day 15 from TNF-alpha-induced liver degeneration. To investigate the importance of RelA in innate immunity, we genetically suppressed this embryonic lethality by breeding the RelA deficiency onto a TNFR type 1 (TNFR1)-deficient background. TNFR1/RelA-deficient mice were born healthy, but were susceptible to bacterial infections and bacteremia and died within a few weeks after birth. Hemopoiesis was intact in TNFR1/RelA-deficient newborns, but neutrophil emigration to alveoli during LPS-induced pneumonia was severely reduced relative to that in wild-type or TNFR1-deficient mice. In contrast, radiation chimeras reconstituted with RelA or TNFR1/RelA-deficient hemopoietic cells were healthy and demonstrated no defect in neutrophil emigration during LPS-induced pneumonia. Analysis of RNA harvested from the lungs of mice 4 h after LPS insufflation revealed that the induction of several genes important for neutrophil recruitment to the lung was significantly reduced in TNFR1/RelA-deficient mice relative to that in wild-type or TNFR1-deficient mice. These results suggest that TNFR1-independent activation of RelA is essential in cells of nonhemopoietic origin during the initiation of an innate immune response.
authors.affiliation: Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: E
authors.initials: E
authors.lastname: Alcamo
authors.forename: J P
authors.initials: JP
authors.lastname: Mizgerd
authors.forename: B H
authors.initials: BH
authors.lastname: Horwitz
authors.forename: R
authors.initials: R
authors.lastname: Bronson
authors.forename: A A
authors.initials: AA
authors.lastname: Beg
authors.forename: M
authors.initials: M
authors.lastname: Scott
authors.forename: C M
authors.initials: CM
authors.lastname: Doerschuk
authors.forename: R O
authors.initials: RO
authors.lastname: Hynes
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D005260:Female; D005313:Fetal Death / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D018390:Gene Targeting; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000235:genetics; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011828:Radiation Chimera / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D016019:Survival Analysis; D013864:Thioglycolates / Q000633:toxicity; D051996:Transcription Factor RelA
chemical_list: D015703:Antigens, CD; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D013864:Thioglycolates; D051996:Transcription Factor RelA