A network-based analysis of systemic inflammation in humans.
Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.
Calvano
Steve E
SE
Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Xiao
Wenzhong
W
Richards
Daniel R
DR
Felciano
Ramon M
RM
Baker
Henry V
HV
Cho
Raymond J
RJ
Chen
Richard O
RO
Brownstein
Bernard H
BH
Cobb
J Perren
JP
Tschoeke
S Kevin
SK
Miller-Graziano
Carol
C
Moldawer
Lyle L
LL
Mindrinos
Michael N
MN
Davis
Ronald W
RW
Tompkins
Ronald G
RG
Lowry
Stephen F
SF
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D019295:Computational Biology; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D004731:Endotoxins; D012333:RNA, Messenger