Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-kappa B in leukocyte recruitment - PubMed (original) (raw)

Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-kappa B in leukocyte recruitment

E Alcamo et al. J Immunol. 2001.

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.

PubMed Disclaimer

Cited by

Immune Biomarkers at Birth Predict Lower Respiratory Tract Infection Risk in a Large Birth Cohort.
Mondell E, Nino G, Hong X, Wang X, Gutierrez MJ. Mondell E, et al. Pathogens. 2024 Sep 5;13(9):765. doi: 10.3390/pathogens13090765. Pathogens. 2024. PMID: 39338956 Free PMC article.
Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases.
Pasparakis M. Pasparakis M. Nat Rev Immunol. 2009 Nov;9(11):778-88. doi: 10.1038/nri2655. Nat Rev Immunol. 2009. PMID: 19855404 Review.
The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms.
Gugasyan R, Voss A, Varigos G, Thomas T, Grumont RJ, Kaur P, Grigoriadis G, Gerondakis S. Gugasyan R, et al. Mol Cell Biol. 2004 Jul;24(13):5733-45. doi: 10.1128/MCB.24.13.5733-5745.2004. Mol Cell Biol. 2004. PMID: 15199130 Free PMC article.
Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia.
Quinton LJ, Jones MR, Simms BT, Kogan MS, Robson BE, Skerrett SJ, Mizgerd JP. Quinton LJ, et al. J Immunol. 2007 Feb 1;178(3):1896-903. doi: 10.4049/jimmunol.178.3.1896. J Immunol. 2007. PMID: 17237440 Free PMC article.
Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice.
Cho HY, Morgan DL, Bauer AK, Kleeberger SR. Cho HY, et al. Am J Respir Crit Care Med. 2007 Apr 15;175(8):829-39. doi: 10.1164/rccm.200509-1527OC. Epub 2007 Jan 25. Am J Respir Crit Care Med. 2007. PMID: 17255564 Free PMC article.

Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-kappa B in leukocyte recruitment - PubMed (original) (raw)