Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans.
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.
Talwar
Shefali
S
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1662, USA.
Munson
Peter J
PJ
Barb
Jennifer
J
Fiuza
Carmen
C
Cintron
Anadel Pilar
AP
Logun
Carolea
C
Tropea
Margaret
M
Khan
Sameena
S
Reda
Debra
D
Shelhamer
James H
JH
Danner
Robert L
RL
Suffredini
Anthony F
AF
D000328:Adult; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood / Q000276:immunology*; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013997:Time Factors
D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface