The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Many small molecule screens have sought to identify agents that prevent endothelial cell activation. Yet, small molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed which identifies activated endothelium by its capacity to trigger MIP1 beta from primary monocytes. Subsequently, a 642 compound library of 39 distinctive scaffolds generated by diversity oriented synthesis was screened for small molecules that activated the endothelium. From the identified inflammatory compounds, 96 analogs of one particular class of compounds were efficiently prepared by solid phase split-and-pool synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive analogues identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.
- Copyright © 2011 by The American Association of Immunologists, Inc.