Identifying novel mechanisms regulating the expression of the inflammatory chemokine IP-10

Abstract

Abstract In response to the innate immune signals, mammalian cells produce inflammatory cytokines and chemokines to activate the immune system, and their expression is tightly regulated. IFN-gamma Inducible Protein (IP-10), also known as C-X-C motif chemokine 10 (CXCL10), is an inflammatory chemokine belonging to the CXC chemokine family. IP-10 is chemotactic for neutrophils, and altered expression of IP-10 is associated with many inflammatory diseases. Fli-1 belongs to the ETS transcription factor family. We have demonstrated that the Fli-1 transcription factor is a novel regulator in modulating the expression of many inflammatory mediators, including monocyte chemotactic protein 1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5) and interleukin 6 (IL-6). In this report, we found that murine endothelial cells transfected with Fli-1 specific siRNA produced significantly lower IP-10 after stimulation with Toll-like receptor 4 ligand LPS compared to the cells transfected with control siRNA. The production of IP-10 in endothelial cells with LPS stimulation is dose-dependent. We demonstrated that Fli-1 binds to the IP-10 promoter by Chromatin immunoprecipitation (ChIP) assay. Mechanisms by which Fli-1 regulates expression of IP-10 are currently being investigated. Together, the results indicate that Fli-1 is a novel, critical transcription factor in regulating the expression of the pro-inflammatory chemokine IP-10