Activated monocytes and macrophages are key cell types responsible for the deleterious host responses in Gram-negative sepsis. Lipopolysaccharide (LPS) from Gram-negative bacteria induces a number of inflammatory target genes in monocytes and macrophages. The zinc-finger transcription factor Egr-1 is induced by LPS in these cell types. We have recently demonstrated that LPS induces tissue factor and TNFa, in part, via induction of Egr-1 in THP-1 monocytic cells and human monocytes. However, the role of Egr-1 in sepsis is not clear. This study will use a novel in vivo targeting approach to identify key target genes of Egr-1 in LPS stimulated monocytes. In addition, we will use Egr-1 -/- mice to identify Egr-1 target genes. Finally, the role of Egr-1 in sepsis will be addressed by challenging Egr-1 -/- vs. Egr-1 +/+ mice with various doses of LPS and monitoring the survival of these mice.
