Stimulus-specific regulation of chemokine expression involves differentialactivation of the redox-responsive transcription factors AP-1 and NF-kappaB

The promoters of the: IL-8, MCP-1, and RANTES genes contain binding sites f or the redox-responsive transcription factors AP-1 and NF-kappa B, which ha ve been shown to be important for their expression. In this overview, we pr esent evidence from our laboratories that the stimulus-specific regulation of these chemokines by the reactive oxidant H2O2, the proinflammatory cytok ine TNF-alpha, and respiratory syncytial virus (RSV) is mediated in a cell type-specific manner involving different patterns of AP-1 and NF-kappa B bi nding activity. Our results demonstrate that H2O2 induction of IL-8 gene ex pression is linked with the selective binding of AP-1 to the IL-8 promoter, whereas TNF-alpha and RSV induction of IL-8 correlates with the activation of NF-kappa B binding. We propose that the differential activation and bin ding of inducible transcription factors to the promoter regions of chemokin e genes provides a critical regulatory mechanism by which the CXC and CC ch emokines call be selectively expressed in a cell type-specific and stimulus -specific maimer. Such a regulatory mechanism of differential chemokine exp ression could critically influence the site-specific recruitment of distinc t subsets of leukocytes to sites of inflammation and injury.