Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model.
In septic shock, tissue factor (TF) activates blood coagulation, and cytokines and chemokines orchestrate an inflammatory response. In this study, the role of Egr-1 in lipopolysaccharide (LPS) induction of TF and inflammatory mediators in vivo was evaluated using Egr-1(+/+) and Egr-1(-/-) mice. Administration of LPS transiently increased the steady-state levels of Egr-1 mRNA in the kidneys and lungs of Egr-1(+/+) mice with maximal induction at one hour. Egr-1 was expressed in epithelial cells in the kidneys and lungs in untreated and LPS-treated mice. LPS induction of monocyte chemoattractant protein mRNA in the kidneys and lungs of Egr-1(-/-) mice was not affected at 3 hours, but its expression was significantly reduced at 8 hours compared with the expression observed in Egr-1(+/+) mice. Similarly, LPS induction of TF mRNA expression in the kidneys and lungs at 8 hours was reduced in Egr-1(-/-) mice. However, Egr-1 deficiency did not affect plasma levels of tumor necrosis factor alpha in endotoxemic mice. Moreover, Egr-1(+/+) and Egr-1(-/-) mice exhibited similar survival times in a model of acute endotoxemia. These data indicate that Egr-1 does not contribute to the early inflammatory response in the kidneys and lungs or the early systemic inflammatory response in endotoxemic mice. However, Egr-1 does contribute to the sustained expression of inflammatory mediators and to the maximal expression of TF at 8 hours in the kidneys and lungs.
Pawlinski
Rafal
R
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA.
Pedersen
Brian
B
Kehrle
Bettina
B
Aird
William C
WC
Frank
Rolf D
RD
Guha
Mausumee
M
Mackman
Nigel
N
D000818:Animals; D015152:Blotting, Northern; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1; D019446:Endotoxemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017874:Immediate-Early Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013925:Thromboplastin / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014158:Transcription, Genetic; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D013925:Thromboplastin