Gram-negative bacterial infections release LPS into the bloodstream that activates monocytes (Figure 5). These cells express various inflammatory mediators, including the cytokines TNF-alpha and IL-6. In addition, they express the procoagulant molecule TF to "clot off" the infection and reduce dissemination of the bacteria. However, over-reaction to LPS can lead to septic shock. We are studying the role of various intracellular signaling pathways and transcription factors, such as AP-1, NF-kB, and Egr-1, in the induction of these genes. In addition, we are characterizing endogenous anti-inflammatory pathways and transcription factors, such as the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway, which we have shown reduces LPS induction of TF, TNF-alpha, and IL-6 in monocytic cells.
Figure 5: LPS induction of gene expression in monocytes