Abstract
To define gene expression
profiles that occur during the initial activation of human
innate immunity, we administered intravenous endotoxin (n 8) or
saline (n 4) to healthy subjects and hybridized RNA from blood
mononuclear cells (0, 0.5, 6, 24, 168 h) or whole blood (0, 3, 6, 24,
168 h) to oligonucleotide probe arrays. The greatest change in mononuclear
cell gene expression occurred at 6 h (439 induced and 428
repressed genes, 1% false discovery rate, and 50% fold change)
including increased expression of genes associated with pathogen
recognition molecules and signaling cascades linked to receptors
associated with cell mobility and activation. Induced defense response
genes included cytokines, chemokines, and their respective receptors,
acute-phase transcription factors, proteases, arachidonate metabolites,
and oxidases. Repressed defense response genes included those associated
with co-stimulatory molecules, T and cytotoxic lymphocytes,
natural killer (NK) cells, and protein synthesis. Gene expression
profiles of whole blood had similar biological themes. Over 100 genes
not typically associated with acute inflammation were differentially
regulated after endotoxin. By 24 h, gene expression had returned to
baseline values. Thus the inflammatory response of circulating leukocytes
to endotoxin in humans is characterized by a rapid amplification
and subsidence of gene expression. These results indicate that
a single intravascular exposure to endotoxin produces a large but
temporally short perturbation of the blood transcriptome.
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