Early Intervention by Targeting Inhibitors of Multiple Signal Transduction Pathways in LPS Induced Human PBMCs

Abstract

Lipopolysaccharide (LPS) is an endotoxin that induces the secretion of pro‐inflammatory cytokines in many cells which can induce septic shock in humans. This project is aimed at developing a rapid diagnostic method to combat the effects of LPS by utilizing signal transduction pathways induced by LPS in Peripheral Blood Mononuclear Cells (PBMC) as a prototype module. A set of LPS induced genes were identified through micro array analysis and common signaling pathways were found. We blocked key components such as JNK and p38 of these pathways that function as pathway inter‐connectors and then evaluated the extent of alterations to the previously identified gene expression patterns. Further investigation of the pathways led to the identification of common components to multiple pathways that can serve as diagnostic markers. Our main objective was to investigate the effect of two inhibitors on the time dependent gene expression pattern and then the impact on components that are indirectly associated with the inhibited signaling pathways. In addition, we also evaluated the specific inhibitors by correlating the observed gene expression pattern to the protein expression using ELISA. We believe the study will allow us to better understand the complex interactions of multiple signal transduction pathways induced by LPS, and how to combat the effects.