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

Salih Sanlioglu; Carl M Williams; Lobelia Samavati; Noah S Butler; Guoshun Wang; Paul B McCray; Teresa C Ritchie; Gary W Hunninghake; Ebrahim Zandi; John F Engelhardt

doi:10.1074/jbc.M102061200

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

Salih Sanlioglu, Carl M Williams, Lobelia Samavati, Noah S Butler, Guoshun Wang, Paul B McCray, Teresa C Ritchie, Gary W Hunninghake, Ebrahim Zandi and John F Engelhardt

The Journal of biological chemistry, Vol.276(32), pp.30188-30198

08/10/2001

DOI: 10.1074/jbc.M102061200

PMID: 11402028

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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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Title: Subtitle: Lipopolysaccharide Induces Rac1-dependent Reactive Oxygen Species Formation and Coordinates Tumor Necrosis Factor-α Secretion through IKK Regulation of NF-κB
Creators: Salih Sanlioglu
Carl M Williams
Lobelia Samavati
Noah S Butler
Guoshun Wang
Paul B McCray
Teresa C Ritchie
Gary W Hunninghake
Ebrahim Zandi
John F Engelhardt
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.276(32), pp.30188-30198
DOI: 10.1074/jbc.M102061200
PMID: 11402028
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Language: English
Date published: 08/10/2001
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Microbiology and Immunology; Pulmonary Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Radiation Oncology; Internal Medicine
Record Identifier: 9984001151702771

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