Gene expression profiling identifies C/EBPdelta as a candidate regulator of endotoxin-induced disseminated...

A runaway inflammatory response to systemic infection or severe trauma is characterized by the activation of a diversity of pathways, ultimately resulting in the development of disseminated intravascular coagulation (DIC) and multiorgan failure.

Despite increased fundamental knowledge of the pathogenesis of DIC, the exact molecular mechanisms remain elusive. We aimed therefore to improve our understanding of the molecular pathways underlying endotoxin-induced DIC.

We performed large-scale gene expression profiling in the liver of mice during the onset of endotoxin-induced DIC. The relevance of an identified candidate gene involved in endotoxin-induced DIC was subsequently assessed in the generalized Shwartzman reaction.

Approximately 5% of over 20,000 genes were differentially regulated. In addition to well-established sepsis-associated genes, such as macrophage inflammatory protein 1, plasminogen activator inhibitor 1, CD14, and A20, we identified several novel candidates for inflammatory disease of which the transcription factor C/EBPdelta (CAAT/enhancer binding protein delta) was studied further. Induction of DIC in C/EBPdelta-deficient mice decreased endotoxin-induced systemic inflammation as compared with wild-type mice, as evident from decreased plasma levels of tumor necrosis factor-alpha and IL-6. In addition, C/EBPdelta deficiency partly protected against DIC-induced mortality. Interestingly, C/EBPdelta deficiency seemed mainly protective by improving renal function. This latter notion was confirmed in an experimental model of renal ischemia/reperfusion injury in which C/EBPdelta deficiency reduced ischemia/reperfusion-induced creatinine and urea levels.

Our results endorse the usefulness of gene expression profiling in identifying novel mediators of DIC by showing that C/EBPdelta regulates specific pathologic features of this endotoxin-induced syndrome.