Key result
Lipopolysaccharide addition to human whole blood increased expression of multiple inflammation-related genes by 1.5-fold to several 1,000-fold, an effect that was inhibited by dexamethasone.
High-precision gene expression analysis in human whole blood can characterize the distinct molecular mechanisms of different immunosuppressants.
Whole-blood gene expression profiling distinguishes immunosuppressant mechanisms; leaves open translation to in vivo or clinical settings.
Analysis of gene expression is emerging as a valuable tool in drug discovery. Using a gene expression system involving high‐precision quantitative PCR, two robust in vitro models of inflammation in human whole blood were examined. In the first model, lipopolysaccharide (LPS) addition to whole blood resulted in profound changes in the expression of multiple inflammation‐related genes, ranging from increases of 1.5‐fold to several 1,000‐fold. In the second model, stimulation by interleukin 2 plus toxic shock syndrome toxin 1 (IL2+TSST1) resulted in a distinct pattern of expression consistent with increased contributions from T‐lymphocyte activation. Both stimuli resulted in unique, but consistent patterns of gene expression across individual blood donors. In addition, experiments using the immunosuppressive drugs, dexamethasone and cyclosporin A, demonstrated that the distinct mechanisms of different immunosuppresants can be characterized at the molecular level in human whole blood using specific pathway markers. Thus, dexamethasone inhibited induction of gene expression at a number of loci in both models of the inflammatory response, while Cyclosporin A had minimal effects in the LPS model but had profound effects in the IL2+TSST1 model. These findings validate the use of high‐precision gene expression analysis (HPGEA) directly from human whole blood, coupled with well‐defined stimulation parameters, for characterizing, monitoring, and predicting the effects of novel therapeutic agents in pre‐clinical studies. Drug Dev. Res. 63:8–21, 2004.
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Tryon et al. (2004) studied Inflammation (in vitro models). Dexamethasone and Cyclosporin A was evaluated on Gene expression changes. Lipopolysaccharide addition to human whole blood increased expression of multiple inflammation-related genes by 1.5-fold to several 1,000-fold, an effect that was inhibited by dexamethasone.
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