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Infection and Immunity, April 2004, p. 2123-2130, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2123-2130.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Reactive Oxygen and Nitrogen Species Differentially Regulate Toll-Like Receptor 4-Mediated Activation of NF-{kappa}B and Interleukin-8 Expression

Kieran A. Ryan, Michael F. Smith Jr., Michael K. Sanders, and Peter B. Ernst*

Digestive Health Center of Excellence, University of Virginia, Charlottesville, Virginia 22908

Received 29 October 2003/ Returned for modification 2 December 2003/ Accepted 12 January 2004

Toll-like receptor 4 (TLR4) has been identified as a transmembrane protein involved in the host innate immune response to gram-negative bacterial lipopolysaccharide (LPS). Upon activation by LPS recognition, the TIR domain of TLR4 signals through MyD88 to activate the nuclear factor {kappa}B (NF-{kappa}B) pathway, a critical regulator of many proinflammatory genes, including interleukin-8 (IL-8). Emerging evidence suggests that reactive oxygen species (ROS) can contribute to diverse signaling pathways, including the LPS-induced cascade. In the present study we investigated the role of ROS in TLR-mediated signaling. Purified Escherichia coli LPS, a highly specific TLR4 agonist, elicited an oxidative burst in the monocyte-like cell line THP-1 in a time- and dose-dependent manner. This oxidative burst was shown to be dependent on the presence of TLR4 through transfection studies in HEK cells, which do not normally express this protein, and with bone marrow-derived macrophages from C3H/HeJ mice, which express a mutated TLR4 protein. LPS-stimulated IL-8 expression could be blocked by the antioxidants N-acetyl-L-cysteine and dimethyl sulfoxide at both the protein and mRNA levels. These antioxidants also blocked LPS-induced IL-8 promoter transactivation as well as the nuclear translocation of NF-{kappa}B. These data provide evidence that ROS regulate immune signaling through TLR4 via their effects on NF-{kappa}B activation.

* Corresponding author. Mailing address: Digestive Health Center of Excellence, Room 1035, MR4 Building, Lane Road, University of Virginia, Charlottesville, VA 22908. Phone: (434) 924-1944. Fax: (434) 982-0044. E-mail: pernst{at}virginia.edu.

Editor: D. L. Burns

Infection and Immunity, April 2004, p. 2123-2130, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2123-2130.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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