Inhibition of lipopolysaccharide-induced interferon regulatory factor 3 activation and protection from septic shock by hydroxystilbenes.
Interferon regulatory factor 3 (IRF3) mediates the transcriptional induction of interferon-stimulated genes (ISGs) in response to viral and bacterial infections. Here we show that the hydroxystilbene piceatannol inhibits the LPS-mediated activation of IRF3 and subsequent ISG induction. Consequently, piceatannol blocks the LPS-induced up-regulation of critical mediators of the inflammatory response such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), and macrophage chemoattractant protein (MCP-1). Furthermore, the LPS-mediated induction of tissue factor (TF), a cell surface protein responsible for initiating the coagulation cascade, is also inhibited by piceatannol. The effectiveness of piceatannol in blocking both the inflammatory response and the coagulation pathway is evidenced by its ability to confer protection against LPS-induced septic shock in a murine model. Thus, IRF3 appears to be a promising target for pharmacologic intervention in the prevention or treatment of septic shock syndrome.
Dang
Oanh
O
Division of Biological Sciences and UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093-0322, USA.
Navarro
Lorena
L
David
Michael
M
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050838:Interferon Regulatory Factor-3; D007372:Interferons / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D018805:Sepsis; D012769:Shock / Q000473:pathology*; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D015850:Interleukin-6; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D013267:Stilbenes; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C041525:3,3',4,5'-tetrahydroxystilbene; D007372:Interferons; D011505:Protein-Tyrosine Kinases; D012260:Ribonucleases