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Cited by 395NF-κB Signaling PathwaysImmune Response and InflammationProtein Kinase Regulation and GTPase Signaling

The DOI matches its Crossref record; 94 of the 94 references it cites were found in a registry or an index.

Lipopolysaccharide Induces Rac1-dependent Reactive Oxygen Species Formation and Coordinates Tumor Necrosis Factor-α Secretion through IKK Regulation of NF-κB

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Sanlioglu, Salih, Williams, Carl M., Samavati, Lobelia, Butler, Noah S., Wang, Guoshun, McCray, Paul B., Ritchie, Teresa C., Hunninghake, Gary W., Zandi, Ebrahim, Engelhardt, John F.·2001·Journal of Biological Chemistry
DOI 10.1074/jbc.m102061200
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Abstract

Reactive oxygen species (ROS) are important second messengers generated in response to many types of environmental stress. In this setting, changes in intracellular ROS can activate signal transduction pathways that influence how cells react to their environment. In sepsis, a dynamic proinflammatory cellular response to bacterial toxins (e.g. lipopolysaccharide or LPS) leads to widespread organ damage and death. The present study demonstrates for the first time that the activation of Rac1 (a GTP-binding protein), and the subsequent production of ROS, constitutes a major pathway involved in NFkappaB-mediated tumor necrosis factor-alpha (TNFalpha) secretion following LPS challenge in macrophages. Expression of a dominant negative mutant of Rac1 (N17Rac1) reduced Rac1 activation, ROS formation, NFkappaB activation, and TNFalpha secretion following LPS stimulation. In contrast, expression of a dominant active form of Rac1 (V12Rac1) mimicked these effects in the absence of LPS stimulation. IKKalpha and IKKbeta were both required downstream modulators of LPS-activated Rac1, since the expression of either of the IKK dominant mutants (IKKalphaKM or IKKbetaKA) drastically reduced NFkappaB-dependent TNFalpha secretion. Moreover, studies using CD14 blocking antibodies suggest that Rac1 induces TNFalpha secretion through a pathway independent of CD14. However, a maximum therapeutic inhibition of LPS-induced TNFalpha secretion occurred when both CD14 and Rac1 pathways were inhibited. Our results suggest that targeting both Rac1- and CD14-dependent pathways could be a useful therapeutic strategy for attenuating the proinflammatory cytokine response during the course of sepsis.

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Research works printed but not linked: 4

  1. Morrison, 1978, Am. J. Pathol., 93, 526
  2. Peppelenbosch, 1999, Blood, 93, 4011, 10.1182/blood.V93.11.4011 · DOI
  3. Shi, 2000, Ann. Clin. Lab. Sci., 30, 209
  4. Ingalls, 1998, Prog. Clin. Biol. Res., 397, 107

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Metadata

Authors
Sanlioglu, S., Williams, C. M., Samavati, L., Butler, N. S., Wang, G., McCray, P. B., Ritchie, T. C., Hunninghake, G. W., Zandi, E., & Engelhardt, J. F.
Affiliations
  • University of Iowa (US)
  • USC Norris Comprehensive Cancer Center (US)
Corresponding author
Engelhardt, John F.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2001-08
Volume
276
Issue
32
Pages
30188-30198
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m102061200
OpenAlex
W2161781385
Cited by
395
References
94
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 9 · 2019: 10 · 2018: 12 · 2017: 4 · 2016: 9 · 2015: 13 · 2014: 17 · 2013: 17 · 2012: 16
FWCI
9.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p50hl060316-05)
  • National Heart, Lung, and Blood Institute (HL 60316)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK54759, P30DK054759)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
lipopolysaccharide, Rac1, reactive oxygen species, NF-κB activation, IKKα, IKKβ, macrophages, CD14, sepsis, dominant negative Rac1
MeSH terms
Adenoviridae, Animals, Catalase, Cell Line, Cell Nucleus, Dose-Response Relationship, Drug, Electron Spin Resonance Spectroscopy, Enzyme Activation, Ethidium, Gene Expression Regulation, Genes, Dominant, Glutathione Transferase, Humans, Lipopolysaccharides, Luciferases, Models, Biological, Mutation, Oxidation-Reduction, Protein Binding, RNA, Messenger, Superoxides, Time Factors, Tumor Necrosis Factor-alpha, Blotting, Western, Signal Transduction, Down-Regulation, Up-Regulation, Cytokines, NF-kappa B, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Lipopolysaccharide Receptors, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, rac1 GTP-Binding Protein, Mice, I-kappa B Kinase

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