+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Regulation of an essential innate immune response by the p50 subunit of NF-kappaB



Regulation of an essential innate immune response by the p50 subunit of NF-kappaB



Journal of Clinical Investigation 102(9): 1645-1652



Recognition of bacterial endotoxin (LPS) elicits multiple host responses, including activation of cells of the innate immune system. LPS exposure occurs repeatedly during septicemia, making strict regulation of gene expression necessary. Such regulation might prevent, for example, the continuous production of proinflammatory cytokines such as tumor necrosis factor (TNF), which could lead to severe vascular collapse. Tolerance to LPS is characterized by a diminished production of TNF during prolonged exposure to LPS, and is therefore likely to represent an essential control mechanism during sepsis. In the present study, which uses mice with genetic deletions of the proteins of NF-kappaB complex, we provide data demonstrating that increased expression of the p50 subunit of NF-kappaB directly results in the downregulation of LPS-induced TNF production. This contention is supported by the following observations: (1) tolerance to LPS is not induced in macrophages from p50-/- mice; (2) long-term pretreatment with LPS does not block synthesis of TNF mRNA in p50-/- macrophages (in contrast to wild-type macrophages); (3) ectopic overexpression of p50 reduces transcriptional activation of the murine TNF promoter; and (4) analysis of the four kappaB sites from the murine TNF promoter demonstrates that binding of p50 homodimers to the positively acting kappaB3 element is associated with development of the LPS-tolerant phenotype. Thus, p50 expression plays a key role in the development of LPS tolerance.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 011267477

Download citation: RISBibTeXText

PMID: 9802878


Related references

Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes and Development 24(24): 2760-2765, 2011

Down-regulation of NF-kappaB target genes by the AP-1 and STAT complex during the innate immune response in Drosophila. Plos Biology 5(9): E238-E238, 2007

Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF-kappaB. American Journal of Physiology. Lung Cellular and Molecular Physiology 298(6): L744-L754, 2010

p120-catenin expressed in alveolar type II cells is essential for the regulation of lung innate immune response. American Journal of Pathology 185(5): 1251-1263, 2016

Use of an NF-kappaB decoy or use of antisense oligodeoxynucleotides to the Rel A subunit inhibits NF-kappaB expression and suppresses the immune response. Arthritis & Rheumatism 40(9 SUPPL ): S209, Sept, 1997

A critical role for the RelA subunit of nuclear factor kappaB in regulation of multiple immune-response genes and in Fas-induced cell death. Journal of Experimental Medicine 189(6): 999-1004, 1999

NF-kappaB and the innate immune response. Current Opinion in Immunology 12(1): 52-58, 2000

Identification of a novel innate immune response function for NF-kappaB. Journal of Interferon & Cytokine Research 22(Supplement 1): S-88-S-89, 2002

Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. Cytokine & Growth Factor Reviews 18(5-6): 483-490, 2007

The role of Toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation. Postepy Higieny i Medycyny Doswiadczalnej 60: 52-63, 2006

Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-kappaB activation and enhancing SOCS1 expression. Immunology Letters 125(2): 151-155, 2009

Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response. Clinical Immunology 138(3): 299-310, 2011

Hepatocyte-specific inhibitor-of-kappaB-kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration. Hepatology 47(6): 2036-2050, 2008

SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Research 142(1-2): 19-27, 2009

Stimulatory effect of Eucalyptus essential oil on innate cell-mediated immune response. Bmc Immunology 9: 17, 2008