A network-based analysis of systemic inflammation in humans

Steve E. Calvano, Wenzhong Xiao, Daniel R. Richards, Ramon M. Felciano, Henry V. Baker, Raymond J. Cho, Richard O. Chen, Bernard H. Brownstein, J. Perren Cobb, S. Kevin Tschoeke, Carol Miller-Graziano, Lyle L. Moldawer, Michael N. Mindrinos, Ronald W. Davis (), Ronald G. Tompkins and Stephen F. Lowry
Additional contact information
Steve E. Calvano: UMDNJ-Robert Wood Johnson Medical School
Wenzhong Xiao: Stanford Genome Technology Center
Daniel R. Richards: Ingenuity Systems Inc
Ramon M. Felciano: Ingenuity Systems Inc
Henry V. Baker: University of Florida College of Medicine
Raymond J. Cho: Ingenuity Systems Inc
Richard O. Chen: Ingenuity Systems Inc
Bernard H. Brownstein: Washington University in St Louis
J. Perren Cobb: Washington University in St Louis
S. Kevin Tschoeke: University of Florida College of Medicine
Carol Miller-Graziano: University of Rochester School of Medicine
Lyle L. Moldawer: University of Florida College of Medicine
Michael N. Mindrinos: Stanford Genome Technology Center
Ronald W. Davis: Stanford Genome Technology Center
Ronald G. Tompkins: Massachusetts General Hospital, Harvard Medical School
Stephen F. Lowry: UMDNJ-Robert Wood Johnson Medical School

Nature, 2005, vol. 437, issue 7061, 1032-1037

Abstract: Abstract Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens1,2,3,4,5. 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.

Date: 2005
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DOI: 10.1038/nature03985

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