Cited by 101Immune Response and InflammationTGF-β signaling in diseasesNF-κB Signaling Pathways

Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-β1 Signaling Pathway

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McCartney-Francis, Nancy, Jin, Wenwen, Wahl, Sharon M·2004·The Journal of Immunology

Abstract

TGF-β1 plays a central role in maintaining normal immune function and deficiency of this potent immunosuppressive molecule is linked to uncontrolled inflammation, cachexia, and multiorgan failure as seen in the TGF-β1 null mouse. Infiltration of inflammatory cells into vital organs of the null mouse is accompanied by increased gene expression of inflammatory cytokines, including TNF-α and IL-1β, as well as inducible NO synthase, each regulated by NF-κB. Treatment with the proteasome inhibitor MG132 to prevent NF-κB activation dramatically reduced NO production and expression of inflammatory cytokines. This inflammatory phenotype with NF-κB activation in the TGF-β1 null mouse, in the absence of any identifiable pathogen, suggested activation of innate immune responses. Because Toll-like receptors (TLR) are essential in the activation of innate immunity, we examined inflamed tissue from TGF-β1 null and wild-type mice for expression of TLR4, the receptor that interacts with bacterial cell wall LPS to initiate an NF-κB-dependent signaling pathway, leading to gene transcription of inflammatory mediators. Increased TLR4 mRNA expression observed in TGF-β1 null mice as well as in mice lacking the TGF-β transcription factor Smad3 was associated with LPS hyperresponsiveness leading to increased expression of inflammatory cytokines and NO and endotoxemia. Furthermore, mice lacking both TGF-β1 and a functional TLR4 were resistant to endotoxin shock. Constitutive and/or environmental activation of TLR4 and downstream elements, in the absence of TGF-β suppression, may impact on innate and adaptive immunity and contribute to massive uncontrolled inflammation.

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Crossref · 10.4049/jimmunol.172.6.3814

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Authors
McCartney-Francis, N., Jin, W., & Wahl, S. M.
Affiliations
National Institutes of Health (US)
Venue
The Journal of Immunology
Published
2004-03
Volume
172
Issue
6
Pages
3814-3821
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W1768438545
Cited by
101
References
43
Citations by year
2026: 1 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 5
FWCI
4.46
Type
journal article
Language
en
Open access
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
TGF-β1, TLR4, endotoxemia, NF-κB activation, Smad3, nitric oxide, inflammatory cytokines, innate immunity, uncontrolled inflammation
MeSH terms
Animals, Immunity, Innate, Inflammation, Injections, Intraperitoneal, Lipopolysaccharides, Membrane Glycoproteins, Mice, Inbred C3H, Mice, Inbred C57BL, Multiple Organ Failure, Nitric Oxide, Phenotype, Receptors, Cell Surface, Signal Transduction, Up-Regulation, Transforming Growth Factor beta, NF-kappa B, Mice, Knockout, Endotoxemia, Toll-Like Receptors, Toll-Like Receptor 4, Mice, Transforming Growth Factor beta1

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